单核苷酸多态性分析准确预测特发性自闭症小鼠模型海马活动和记忆能力的多种损伤-动脉网

Single-nucleotide polymorphism analysis accurately predicts multiple impairments in hippocampal activity and memory performance in a murine model of idiopathic autism

Nature 等信源发布 2025-01-04 16:26

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可切换为仅中文

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Abstract

摘要

Autism spectrum disorder (ASD) comprises alterations in brain anatomy and physiology that ultimately affect information processing and behavior. In most cases, autism is considered idiopathic, involving alterations in numerous genes whose functions are not extensively documented. We evaluated the C58/J mouse strain as an idiopathic model of ASD, emphasizing synaptic transmission as the basis of information processing.

自闭症谱系障碍（ASD）包括大脑解剖和生理的改变，最终影响信息处理和行为。在大多数情况下，自闭症被认为是特发性的，涉及许多功能尚未广泛记录的基因的改变。我们将C58/J小鼠品系评估为ASD的特发性模型，强调突触传递是信息处理的基础。

Through in silico analysis, we found that the C58/J strain carries single nucleotide polymorphisms (SNPs) compared to the C57BL/6J control strain related to synaptic structure and LTP induction. These SNPs have human orthologs previously associated with ASD. We then assessed chemical potentiation (cLTP) in synaptosomes, the electrophysiological properties of hippocampal CA3 cells, and the induction of LTP in .

通过计算机分析，我们发现与与突触结构和LTP诱导相关的C57BL/6J对照菌株相比，C58/J菌株携带单核苷酸多态性（SNP）。这些SNP具有先前与ASD相关的人类直系同源物。。

ex-vivo

离体

slices. An increased proportion of synaptosomes expressing the GluA1 subunit of AMPA receptor and Nrx1β in the membrane was found in the C57BL/6J control strain, but not in C58/J mice, after cLTP induction. Additionally, several electrophysiological properties of CA3 pyramidal cells and hippocampal communication were altered.

切片。在cLTP诱导后，在C57BL/6J对照品系中发现膜中表达AMPA受体GluA1亚基和Nrx1β的突触体比例增加，但在C58/J小鼠中未发现。此外，CA3锥体细胞和海马通讯的几种电生理特性发生了改变。

Behaviorally, C58/J mice exhibited hyperactivity and subtle memory changes. Our results demonstrate that an idiopathic model of ASD exhibits alterations in hippocampal physiology from the cellular to the circuitry and behavioral levels..

在行为上，C58/J小鼠表现出多动症和微妙的记忆变化。我们的研究结果表明，特发性ASD模型表现出海马生理学的改变，从细胞到电路和行为水平。。

Introduction

简介

Autism spectrum disorder (ASD) comprises a group of neurodevelopmental disorders characterized by persistent deficits in social interaction/communication and the presence of repetitive and stereotyped behaviors

自闭症谱系障碍（ASD）包括一组神经发育障碍，其特征是社交互动/沟通持续缺陷以及重复和刻板行为的存在

. The complex etiology of autism is, in most cases (85%), idiopathic

自闭症的复杂病因在大多数情况下（85%）是特发性的

. Interestingly, transcriptome characterization of induced pluripotent stem cells (iPSCs)-derived neurons from individuals with idiopathic autism has revealed a differential expression of ASD-associated genes that participate in several aspects of synaptic transmission, including genes coding for neurotransmitter receptors and genes for scaffolding proteins and cellular adhesion molecules critical for synaptic organization.

有趣的是，来自特发性自闭症患者的诱导性多能干细胞（iPSC）衍生神经元的转录组表征揭示了参与突触传递几个方面的ASD相关基因的差异表达，包括编码神经递质受体的基因以及对突触组织至关重要的支架蛋白和细胞粘附分子的基因。

. Likewise, the ASD-related alterations in electrophysiological activity are linked with variants in genes coding for different types of voltage-sensitive ion channels, including potassium (K

同样，与ASD相关的电生理活性改变与编码不同类型电压敏感离子通道的基因变异有关，包括钾（K

), calcium (Ca

)，钙（约

), and sodium (Na

)，和钠（Na

)

. Impairments in voltage-gated ion channels are of particular interest in the etiology of the frequent co-occurrence of epilepsy and ASD

电压门控离子通道的损伤对癫痫和自闭症频繁并存的病因特别感兴趣

At the neuronal circuit level, long-term potentiation (LTP) at hippocampal Schaffer Collateral-CA1 pyramidal cell synapses (SC-CA1) is impaired in several murine models of syndromic ASD, such as

在神经元回路水平上，在几种综合征型ASD小鼠模型中，海马Schaffer侧支CA1锥体细胞突触（SC-CA1）的长时程增强（LTP）受损，例如

Shank3

haploinsufficiency and

单倍剂量不足和

Shank2

Shank2型

knockout (KO) mice

基因敲除（KO）小鼠

, the Fragile X Syndrome model

，脆弱的X综合征模型

Fmr1

-R138Q mice

-R138Q小鼠

, and the Rett Syndrome model

，以及Rett综合征模型

Mecp2

机械2

KO mice

. Similarly, the autism rat model induced by prenatal exposure to valproate (VPA)

同样，产前暴露于丙戊酸钠（VPA）诱导的自闭症大鼠模型

exhibits impaired LTP at the medial perforant path-dentate gyrus (PP-DG) synapses. Consistent with this, behavioral evaluation of autism models with impaired hippocampal LTP, such as the

在内侧穿孔路径齿状回（PP-DG）突触处表现出LTP受损。与此相一致的是，对海马LTP受损的自闭症模型进行行为评估，例如

Shank3

mutant mice

突变小鼠

, show poor performance in recognition memory, as demonstrated by the novel object recognition test, whereas the

，在识别记忆中表现不佳，如新颖的对象识别测试所示，而

Fmr1

KO mice

KO小鼠

and the VPA exposure-induced mouse model

和VPA暴露诱导的小鼠模型

show decreased contextual fear memory.

表现出情境恐惧记忆下降。

In addition to the core signs, ASD is associated with atypical sensory processing and cognitive deficits in episodic memory, spatial reasoning, and working memory

除了核心体征外，自闭症谱系障碍还与非典型的感觉加工和情景记忆、空间推理和工作记忆中的认知缺陷有关

. Interestingly, neuroimaging studies have also linked these deficits to abnormal brain connectivity, especially in the hippocampus

有趣的是，神经影像学研究也将这些缺陷与异常的大脑连接联系起来，特别是在海马体中

. Therefore, the changes in synaptic plasticity in the hippocampus of animal models of autism may be related to some atypical behaviors

因此，自闭症动物模型海马突触可塑性的变化可能与一些非典型行为有关

The models mentioned above have punctual genetic mutations or, in the case of valproic acid, a well-established teratogenic effect that contributes to autism

上述模型具有准时的基因突变，或者在丙戊酸的情况下，具有公认的致畸作用，从而导致自闭症

. It is thus interesting to determine if an idiopathic model of ASD, which cannot be related to specific causes or mutations, shows alterations at different levels of complexity comprising genetic predictions, synaptic components, circuits, and behavior.

因此，有趣的是，确定与特定原因或突变无关的ASD特发性模型是否显示出不同复杂程度的变化，包括遗传预测，突触成分，电路和行为。

This study aimed to gain insight into the molecular and cellular mechanisms potentially involved in alterations in hippocampal neuronal activity and memory performance in a murine model of idiopathic ASD, the C58/J strain. The autistic-like phenotype of this strain cannot be attributed to a single gene.

这项研究旨在深入了解特发性ASD小鼠模型C58/J株中可能涉及海马神经元活动和记忆表现改变的分子和细胞机制。。

Instead, C58/J mice exhibit polymorphisms in several genes involved in structural plasticity and neurogenesis, along with a complex neurobiology that includes changes in dendrite and spine morphology, neuronal cytoskeletal protein content, hippocampal neurogenesis, neuroinflammation-related markers, and atypical volumes in various brain structures.

相反，C58/J小鼠在涉及结构可塑性和神经发生的几个基因中表现出多态性，以及复杂的神经生物学，包括树突和脊柱形态，神经元细胞骨架蛋白含量，海马神经发生，神经炎症相关标志物和各种脑结构中非典型体积的变化。

Using this model, we performed an in silico approach to predict whether genes involved in the regulation of synaptic transmission carried single-nucleotide polymorphisms (SNPs), and based on these predictions, we assessed the electrical properties of hippocampal CA3 pyramidal cells (PCs), the Mossy Fiber-mediated long-term potentiation (MF LTP) and hippocampal potentiation via chemical induction, along with the performance in hippocampus-dependent memory tasks.

使用该模型，我们进行了计算机模拟方法来预测参与突触传递调控的基因是否携带单核苷酸多态性（SNP），并基于这些预测，我们评估了海马CA3锥体细胞（PC）的电特性，苔藓纤维介导的长时程增强（MF-LTP）和通过化学诱导的海马增强，以及海马依赖性记忆任务的表现。

Our data demonstrate that several genetic alterations commonly found in idiopathic ASD alter hippocampal synaptic capability and may potentially lead to memory changes in the C58/J strain..

我们的数据表明，特发性ASD中常见的几种遗传改变会改变海马突触能力，并可能导致C58/J菌株的记忆改变。。

Results

结果

C58/J mice display single-nucleotide polymorphisms (SNPs) in synaptic genes associated with ASD

C58/J小鼠在与ASD相关的突触基因中显示单核苷酸多态性（SNP）

We first used an in silico approach to investigate potential changes in genes involved in intrinsic excitability and synaptic transmission in the C58/J mouse strain, compared to the C57BL/6J control strain, using the Sanger4 Dataset from the MPD platform

我们首先使用计算机模拟方法，使用MPD平台的Sanger4数据集，研究了与C57BL/6J对照品系相比，C58/J小鼠品系内在兴奋性和突触传递相关基因的潜在变化

. At the synaptic level, we focused on identifying SNPs in genes encoding proteins expressed within the pre- and postsynaptic compartments and presynaptic vesicles

在突触水平上，我们专注于鉴定编码在突触前和突触后区室以及突触前囊泡中表达的蛋白质的基因中的SNP

In the C58/J mice, our in silico analysis revealed changes in 213 presynaptic genes, 544 postsynaptic genes, and 184 presynaptic vesicle genes carrying at least one non-synonymous SNP in coding regions (Cn SNPs) compared to the C57BL/6J strain (Fig.

在C58/J小鼠中，我们的计算机分析显示，与C57BL/6J菌株相比，在编码区（Cn SNP）中携带至少一个非同义SNP的213个突触前基因，544个突触后基因和184个突触前囊泡基因发生了变化（图）。

A; Supplementary Table

A、补充表格

S1级

), highlighting differences in synaptic structure components.

)，突出了突触结构成分的差异。

Fig. 1

图1

Synaptic genes with coding non-synonymous SNPs in the C58/J strain. (

在C58/J菌株中具有编码非同义SNP的突触基因。（笑声）(

) Genes with coding non-synonymous SNPs (Cn SNPs) in C58/J mice encode proteins found in the presynaptic and the postsynaptic compartments and presynaptic vesicles based on data from the Synaptome.db database. (

)根据Synaptome.db数据库的数据，在C58/J小鼠中具有编码非同义SNP（Cn SNP）的基因编码在突触前和突触后区室以及突触前囊泡中发现的蛋白质。（笑声）(

B类

) 62 synaptic genes with Cn SNPs in C58/J mice have human orthologs associated with ASD. (

)C58/J小鼠中具有Cn SNP的62个突触基因具有与ASD相关的人类直系同源物。（笑声）(

C级

) Synaptic genes associated with ASD have between 1 and 16 Cn SNPs in C58/J mice when compared to the C57BL/6J control strain. (

)。（笑声）(

) Top 20 enriched GO terms in the

)前20个丰富的GO术语

Biological process

生物过程

category, resulting from the enrichment analysis of the 62 synaptic genes with Cn SNPs in C58/J mice associated with ASD. (

类别，由与ASD相关的C58/J小鼠中具有Cn SNP的62个突触基因的富集分析得出。（笑声）(

) 15 genes associated with LTP and 5 genes associated with K + channels have between 1 and 16 Cn SNPs in C58/J mice when compared to the control C57 BL/6J strain. (

)与对照C57 BL/6J菌株相比，与LTP相关的15个基因和与K++通道相关的5个基因在C58/J小鼠中具有1至16个Cn SNP。（笑声）(

F级

) Top 20 enriched GO terms in the

)前20个丰富的GO术语

Biological process

生物过程

category resulting from the enrichment analysis of the 15 genes with Cn SNPs in C58/J mice associated with LTP. Top 10 enriched GO terms in the

由与LTP相关的C58/J小鼠中具有Cn SNP的15个基因的富集分析得出的类别。十大丰富GO术语

Molecular function

分子功能

category resulting from the enrichment analysis of the Red module and (

红色模块和(

克

) the Blue module (

)(

小时

) determined by gene clustering within the STRING protein–protein interaction network (PPI) of genes with Cn SNPs associated with synapses, LTP and K + channels. (

)由具有与突触，LTP和K++通道相关的Cn SNP的基因的STRING蛋白质-蛋白质相互作用网络（PPI）内的基因聚类确定。（笑声）(

我

) Enriched GO terms in the

)丰富的GO术语

Human Phenotype Ontology

人类表型本体论

, resulting from the enrichment analysis of the 62 synaptic genes with Cn SNPs in C58/J mice associated with ASD. The number of genes found in each GO term is indicated in parentheses. See methods section for

，这是通过对与ASD相关的C58/J小鼠中62个突触基因与Cn SNP的富集分析得出的。括号中显示了每个GO术语中发现的基因数量。参见方法部分

Gene ratio

基因比率

and

和

Rich factor

丰富的因素

definitions.

定义。

Full size image

全尺寸图像

We also searched for human orthologs of the synaptic genes containing Cn SNPs in the C58/J strain using the SFARI GENE database, providing current genomic data from many individuals with autism

我们还使用SFARI基因数据库搜索了C58/J菌株中含有Cn SNP的突触基因的人类直系同源物，提供了许多自闭症患者的当前基因组数据

. We identified 62 synaptic genes carrying between 1 and 16 Cn SNPs with orthologs previously associated with ASD (Fig.

我们鉴定了62个携带1至16个Cn SNP的突触基因，这些基因具有先前与ASD相关的直系同源物（图）。

B, Supplementary Table

B、补充表格

S1级

). The gene

)。基因

Disc1

showed the highest enrichment of SNPs (Fig.

显示出最高的SNP富集（图）。

C, Supplementary Table

C、补充表格

S1级

). Furthermore, among these 62 genes, 7 have a strong association with autism (score 1) and are particularly relevant for ASD compared to other neurodevelopmental disorders, as indicated by the moderate to strong EAGLE scores. These genes include

)。此外，在这62个基因中，有7个与自闭症有很强的关联（得分1），与其他神经发育障碍相比，与ASD特别相关，如中度至重度EAGLE得分所示。这些基因包括

ANK2, ASXL3, MYT1L, NF1, NRXN3, SCN2A,

ANK2，ASXL3，MYT1L，NF1，NRXN3，SCN2A，

and

和

SHANK2

SHANK2型

(Fig.

（图。

B, Supplementary Table

B、补充表格

S1级

Next, we performed a Gene Ontology (GO) enrichment analysis for the 62 ASD-associated synaptic genes. As expected, the enriched terms obtained in the

接下来，我们对62个与ASD相关的突触基因进行了基因本体论（GO）富集分析。正如预期的那样，在

Biological Process

生物过程

category were associated with nervous system development, cell adhesion, cell communication, and glutamatergic transmission. Additionally, terms related to behavior and learning were enriched (Fig.

类别与神经系统发育，细胞粘附，细胞通讯和谷氨酸能传递有关。此外，与行为和学习相关的术语也得到了丰富（图）。

D, Supplementary Table

D、补充表格

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We also searched for Cn SNPs in genes encoding proteins essential for the induction of LTP in humans

我们还搜索了编码人类LTP诱导所必需蛋白质的基因中的Cn SNP

, and Cn SNPs in genes that exhibit differential expression during induction of LTP in mice

，以及在小鼠LTP诱导过程中表现出差异表达的基因中的Cn SNP

. We identified 15 genes associated with LTP that carried between 1 and 16 Cn SNPs in the C58/J strain. Among these genes, the orthologs of

我们鉴定了15个与LTP相关的基因，这些基因在C58/J菌株中携带1至16个Cn SNP。在这些基因中，直系同源基因

Cacna1c

卡纳1c

and

和

Itpr1

ITPR1

have been previously associated with ASD

以前与自闭症有关

(Fig.

（图。

E, Supplementary Table

E、补充表格

S1级

). Also, the GO enrichment analysis for LTP-associated genes with Cn SNPs in the C58/J strain identified enriched terms in the

)。此外，对C58/J菌株中具有Cn SNP的LTP相关基因的GO富集分析确定了

Biological Process

生物过程

category related to ion transport, ligand-gated ion channel signaling pathways, and ion transmembrane transport (Fig.

与离子转运，配体门控离子通道信号通路和离子跨膜转运有关的类别（图）。

F, Supplementary Table

F、补充表格

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). Consistent with these findings, we also identified a series of genes encoding subunits of potassium channels (KCN)

)。与这些发现一致，我们还鉴定了一系列编码钾通道（KCN）亚基的基因

that carried Cn SNPs in the C58/J strain. We identified 5 KCN-associated genes carrying between 1 and 3 Cn SNPs in C58/J mice; among them, the orthologs of

在C58/J菌株中携带Cn SNP。我们在C58/J小鼠中鉴定出5个携带1至3个Cn SNP的KCN相关基因；其中，直系同源物

Kcnj10

and

和

Kcns3,

Kcns3，

which are also associated with ASD in humans (Fig.

这也与人类的ASD有关（图）。

E, Supplementary Table

E、补充表格

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Next, we assessed whether the proteins encoded by genes carrying Cn SNPs and which were associated with pre- and postsynaptic terminals, LTP induction, and K

接下来，我们评估了携带Cn SNP的基因编码的蛋白质是否与突触前和突触后末端，LTP诱导和K相关

channels could interact to form a functional protein network

通道可以相互作用形成功能性蛋白质网络

. The resulting Protein–Protein interaction network comprised 598 nodes and 321 interaction edges. To identify the most proximal interactions within the largest network, we applied a clustering analysis

由此产生的蛋白质-蛋白质相互作用网络包括598个节点和321个相互作用边缘。为了确定最大网络中最接近的交互，我们应用了聚类分析

resulting in three clusters categorized as red (261 nodes, 105 edges), blue (176 nodes, 75 edges), and green (161 nodes, 111 edges) modules (Supplementary Fig.

产生三个聚类，分别为红色（261个节点，105个边缘），蓝色（176个节点，75个边缘）和绿色（161个节点，111个边缘）模块（Supplementary Fig.）。

A, Supplementary Table

A、补充表格

S1级

). We identified the molecular mechanisms potentially regulated by the protein network in each module using the GO enrichment analysis. The red module showed enrichment in cytoskeleton-binding proteins (Fig.

)。我们使用GO富集分析确定了每个模块中蛋白质网络可能调控的分子机制。红色模块显示细胞骨架结合蛋白富集（图）。

G). The blue module showed enriched terms related to ion binding and ion transmembrane transporter activity (Fig.

G）。蓝色模块显示了与离子结合和离子跨膜转运蛋白活性相关的丰富术语（图）。

H), while the green module was enriched in nucleotide and macromolecule binding (Supplementary Fig.

H），而绿色模块富含核苷酸和大分子结合（Supplementary Fig.）。

B, Supplementary Table

B、补充表格

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Lastly, we conducted the GO enrichment analysis in the

最后，我们在

Human Phenotype Ontology

人类表型本体论

, which provides data on genes associated with human phenotypic abnormalities. The analysis of the group of synaptic genes with Cn SNPs in the C58/J strain resulted in the enrichment of the term 'autistic behavior.' Interestingly, other enriched terms were also related to the dysgenesis of the hippocampus, abnormal hippocampal morphology, precocious puberty, and self-mutilation, which are frequent alterations in individuals with ASD (Fig. .

，它提供了与人类表型异常相关的基因的数据。对C58/J菌株中具有Cn SNP的突触基因组的分析导致“自闭症行为”一词的丰富有趣的是，其他丰富的术语也与海马发育不全，海马形态异常，性早熟和自残有关，这是ASD患者的常见改变（图。

I, Supplementary Table

一、补充表格

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Chemically induced LTP is impaired in hippocampal synaptosomes from the C58/J strain

化学诱导的LTP在C58/J株的海马突触体中受损

If strengthening of a synapse is a necessary step for the induction of LTP, then the dysregulation of the synaptic proteins at the presynaptic and postsynaptic loci of the C58/J strain should compromise synaptic potentiation. To test this prediction, we evaluated the capability of hippocampal synaptosomes to express chemical potentiation or chemical LTP (cLTP).

如果加强突触是诱导LTP的必要步骤，那么C58/J菌株突触前和突触后位点的突触蛋白失调应损害突触增强作用。为了测试这一预测，我们评估了海马突触体表达化学增强或化学LTP（cLTP）的能力。

This form of synaptic potentiation is dependent on NMDA receptors, leads to the postsynaptic recruitment of AMPA receptors (AMPARs), and is accompanied by an increased expression of cellular adhesion molecules at the presynaptic terminal, such as neurexin-1β (Nrx1β). Insertion of AMPARs and increased expression of Nrx1β are necessary steps to induce hippocampal LTP.

这种形式的突触增强依赖于NMDA受体，导致AMPA受体（AMPARs）的突触后募集，并伴随着突触前末端细胞粘附分子（如神经毒素-1β（Nrx1β））的表达增加。AMPARs的插入和Nrx1β的表达增加是诱导海马LTP的必要步骤。

Therefore, we conducted a Fluorescence Analysis of Single-Synapse Long-Term Potentiation (FASS-LTP) protocol in hippocampal synaptosomes isolated from C58/J and control (C57BL/6J) strains. Interestingly, the basal expression of the GluA1 subunit of AMPAR and Nrx1β was significantly increased in synaptosomes from the C58/J strain compared to C57BL/6J synaptosomes (% GluA1 + /Nrx1β + in C57BL/6J = 100.0 ± 14.22%; in C58/J = 134.6 ± 13.29%, *p = 0.0120; Fig. .

因此，我们对从C58/J和对照（C57BL/6J）菌株分离的海马突触体进行了单突触长时程增强（FASS-LTP）方案的荧光分析。；在C58/J=134.6±13.29%中*p=0.0120；图。

A, C57BL/6J basal and C58/J basal, left quadrants, and 2B). Then, the synaptosomes were treated with glycine and a high concentration of external K

A、 C57BL/6J基础和C58/J基础，左象限和2B）。然后，用甘氨酸和高浓度的外部K处理突触体

to induce cLTP. Following this pharmacological manipulation, the proportion of GluA1

诱导cLTP。经过这种药理操作，GluA1的比例

/Nrx1β

Nrx1b

increased ≈ twofold in the C57BL/6J strain, indicating synaptic potentiation (% GluA1 + /Nrx1β + in C57BL/6J basal = 100.0 ± 14.22%; in C57BL/6J cLTP = 337.5 ± 138.4%, *p = 0.0005; Fig.

C57BL/6J菌株增加了约两倍，表明突触增强（C57BL/6J基础中GluA1+/Nrx1β+=100.0±14.22%；在C57BL/6J cLTP中=337.5±138.4%*p=0.0005；图。

A, C57BL/6J basal and cLTP, upper quadrants, and Fig.

A、 C57BL/6J基底和cLTP，上象限和图。

C). In contrast, the glycine + high K

C）。相反，甘氨酸+高K

treatment in the C58/J strain did not alter the proportion of GluA1

C58/J菌株的处理不会改变GluA1的比例

/Nrx1β

Nrx1b

compared to their basal condition (Fig.

与他们的基础条件相比（图）。

A, C58/J basal and cLTP, down quadrants, and Fig.

A、 C58/J基底和cLTP，下象限和图。

C). Notably, the proportion of GluA1

C）。值得注意的是，GluA1的比例

/Nrx1β

Nrx1b

synaptosomes in cLTP conditions was significantly lower in the C58/J strain compared to C57BL/6J mice (% GluA1 + /Nrx1β + in C57BL/6J cLTP = 337.5 ± 138.4%; in C58/J cLTP = 75.40 ± 23.22%, *p = 0.0012; Fig.

与C57BL/6J小鼠相比，C58/J品系在cLTP条件下的突触体明显较低（C57BL-6J cLTP弯曲中的%GluA1*+*/Nrx1β*+=337.5±138.4%；C58/J cLTP。

A, C57BL/6J cLTP and C58/J cLTP, right quadrants, and Fig.

A、 C57BL/6J cLTP和C58/J cLTP，右象限和图。

C). These results suggest decreased levels of synaptic potentiation in the C58/J strain compared to the C57BL/6J strain.

C）。这些结果表明，与C57BL/6J菌株相比，C58/J菌株的突触增强水平降低。

Fig. 2

图2

The cLTP is impaired in hippocampal synaptosomes isolated from C58/J mice. (

从C58/J小鼠分离的海马突触体中cLTP受损。（笑声）(

) Representative density plots showing the detection of the GluA1 subunit of AMPAR and Nrx1β in the membrane of size-gated synaptosomes under basal conditions and after chemically induced LTP (cLTP) in both C57BL/6J and C58/J strains. The upper right quadrant containing GluA1 + / Nrx1β + synaptosomes is indicated by the purple rectangle in each condition.

)代表性密度图显示在基础条件下以及在C57BL/6J和C58/J菌株中化学诱导LTP（cLTP）后，在大小门控突触体膜中检测到AMPAR和Nrx1β的GluA1亚基。在每种情况下，包含GluA1+/Nrx1β++突触体的右上象限由紫色矩形表示。

Fluorescence signals were collected using log amplification. (.

使用对数扩增收集荧光信号。（。

B类

) Bar plot summarizing the percentage of GluA1 + /Nrx1β + synaptosomes under basal conditions. Results were normalized to the C57BL/6J group. C58/J mice showed an increase in GluA1 + /Nrx1β + synaptosomes. (

)条形图总结了基础条件下GluA1+/Nrx1β++突触体的百分比。结果标准化为C57BL/6J组。C58/J小鼠显示GluA1+/Nrx1β++突触体增加。（笑声）(

C级

) Bar plot summarizing the percentage of GluA1 + /Nrx1β + synaptosomes under basal conditions and after chemically induced LTP (cLTP), in both C57BL/6J and C58/J mice. Note that C58/J mice do not display an increase in the percentage of GluA1 + /Nrx1β + synaptosomes after cLTP induction. Results were normalized to the basal conditions of the corresponding group.

)条形图总结了C57BL/6J和C58/J小鼠在基础条件下和化学诱导的LTP（cLTP）后GluA1+/Nrx1β++突触体的百分比。请注意，在cLTP诱导后，C58/J小鼠的GluA1+/Nrx1β++突触体百分比没有增加。将结果标准化为相应组的基础条件。

n = 4 animals in both strains. Bar plots represent the group mean ± S.D. Each symbol within the bars represents an individual animal. *p < 0.05. Additional details of statistical analyses are in Supplementary Table .

两种菌株中有4只动物。条形图代表组平均值±S.D。条形图中的每个符号代表一只动物*p<0.05。统计分析的其他细节见补充表。

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CA3 pyramidal cells of C58/J mice exhibit altered electrophysiological properties

C58/J小鼠的CA3锥体细胞表现出改变的电生理特性

Given the blunted cLTP found in hippocampal synaptosomes from C58/J mice, we next aimed at identifying changes in the passive and active electrophysiological properties of CA3 pyramidal cells (PCs) in acute brain slices obtained from the dorsal hippocampus of the C58/J strain and C57BL/6J strain (Fig. .

鉴于在C58/J小鼠的海马突触体中发现了钝化的cLTP，我们接下来的目的是鉴定从C58/J株和C57BL/6J株的背侧海马获得的急性脑切片中CA3锥体细胞（PC）的被动和主动电生理特性的变化（图。

A).

A）。

Fig. 3

图3

Membrane properties and intrinsic excitability of CA3 PCs from C57BL/6J and C58/J strain. (

来自C57BL/6J和C58/J菌株的CA3 PC的膜特性和内在兴奋性。（笑声）(

) Confocal microphotograph and post-hoc digital reconstruction of a biocytin-filled CA3b pyramidal cell from a C58/J mouse, showing the typical morphology of the CA3 pyramidal cells. (

)来自C58/J小鼠的生物胞素填充的CA3b锥体细胞的共聚焦显微照片和事后数字重建，显示了CA3锥体细胞的典型形态。（笑声）(

A2类

) Schematic representation of the hippocampal slice showing the stimulation electrode at the mossy fibers (MF) bundle and pipettes placement for whole-cell patch-clamp and extracellular recordings. (

)海马切片的示意图显示了苔藓纤维（MF）束上的刺激电极和移液器放置，用于全细胞膜片钳和细胞外记录。（笑声）(

B类

) Representative voltage traces in response to current injections (I–V curve) acquired at − 75 mV. The arrowheads indicate the decreased latency of the C58/J CA3 PCs to elicit action potentials. Notice the increased sag conductance of the CA3 PCs from C58/J strain (horizontal dashed line). (

)响应于在-75 mV下获得的电流注入（I–V曲线）的代表性电压迹线。箭头表示C58/J CA3 PC引起动作电位的潜伏期降低。注意来自C58/J应变的CA3 PC的下垂电导增加（水平虚线）。（笑声）(

C级

) Averaged I–V plot. Note the decreased inward rectification in the hyperpolarizing interval in the C58/J group. In the C57BL/6J, perfusion of BaCl

)平均I–V图。注意C58/J组超极化间隔内向内整流减少。在C57BL/6J中，BaCl的灌注

, blocked the inward-rectifiyng conductance (grey symbols) (

，阻止了内向整流电导（灰色符号）(

) Violin plots contrasting resting membrane potential (RMP) values. RMP was similar in both experimental groups. (

)小提琴图对比静息膜电位（RMP）值。两个实验组的RMP相似。（笑声）(

) Violin plots summarizing the membrane time constant. No statistical difference was found between experimental groups. (

)小提琴图总结了膜时间常数。实验组之间没有发现统计学差异。（笑声）(

F级

) Representative voltage traces contrasting AP firing in response to the injection of a current ramp. C58/J CA3 PCs exhibited decreased latency to fire AP. (

)代表性的电压迹线对比AP发射以响应电流斜坡的注入。C58/J CA3 PC表现出发射AP的潜伏期降低。（笑声）(

克

) Violin plot summarizing the decreased rheobase current to achieve an AP. (

)小提琴图总结了降低的流变基电流以实现AP。（笑声）(

小时

) Violin plot summarizing the decreased latency to fire an action potential in the C58/J CA3 PCs. n = 16 cells /5 animals; in C57BL/6J, n = 17 cells /6 animals in C58/J. Each symbol within the violin and the I-V plots represents an individual cell’s value, or the group mean ± S.E.M, respectively. *p < .05; **p < .01.

)小提琴图总结了C58/J CA3 PC中激发动作电位的潜伏期降低。n=16个细胞/5只动物；在C57BL/6J中，C58/J中的n=17个细胞/6只动物。小提琴和I-V图中的每个符号分别代表单个细胞的值或组平均值±s.E.M*p<0.05**p<0.01。

Additional details of statistical analyses are in Supplementary Table .

统计分析的其他详细信息见补充表。

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Representative I–V traces (Fig.

代表性的I-V迹线（图）。

B) and the resulting I–V scatter plot (Fig.

B）以及由此产生的I-V散点图（图）。

C) obtained with the whole-cell, patch-clamp technique shows that CA3 PCs from the C58/J strain exhibit a decreased latency to fire action potentials (see arrowheads, Fig.

C）用全细胞获得的膜片钳技术显示，来自C58/J菌株的CA3 PC表现出降低的动作电位潜伏期（参见箭头，图）。

B), an increased sag conductance (dashed lines, Fig.

B），下垂电导增加（虚线，图）。

B), and decreased voltage rectification in response to hyperpolarizing current injections (Fig.

B），以及响应超极化电流注入而降低的电压整流（图）。

B, red traces and Fig.

B、红色痕迹和图。

C, red symbols, *p = 0.048). In a series of additional experiments, K

C、红色符号，*p=0.048）。在一系列额外的实验中，K

-mediated inward rectifying conductances were suppressed in the C57BL/6J strain by perfusing Barium chloride (BaCl

-通过灌注氯化钡（BaCl）抑制C57BL/6J菌株介导的内向整流电导

, 50 µM). Perfusion of BaCl

，50µM）。BaCl灌注

suppressed the inward rectification and linearized the I-V relationship (grey symbols Fig.

。

C), indicating the participation of the inward-rectifier K

C），表示内向整流器K的参与

channel (K

通道（K

红外线

)

. In three additional CA3 PCs from C58/J mice, perfusion of BaCl

.在来自C58/J小鼠的另外三个CA3 PC中，灌注BaCl

did not increase the inward rectification conductance nor did it alter the linear I-V trajectory in the scatter plot (data not shown). Both the increased sag conductance mediated by HCN channels and the decreased inward rectification in the C58/J strain suggest increased excitability of CA3 PC, as previously reported for CA1 and CA3 PCs.

没有增加内向整流电导，也没有改变散点图中的线性I-V轨迹（数据未显示）。如先前报道的CA1和CA3 PC，HCN通道介导的下垂电导增加和C58/J菌株内向整流减少均表明CA3 PC的兴奋性增加。

The analysis of the passive properties of CA3 PCs revealed no changes in the resting membrane potential (RMP) nor the membrane time constant (τ) in the C58/J strain (Fig.

对CA3 PC被动特性的分析显示，C58/J菌株的静息膜电位（RMP）和膜时间常数（τ）没有变化（图）。

D,E). Contrary to these findings, the injection of a current ramp (0–250 pA/75 ms; Fig.

D、 E）。与这些发现相反，注入电流斜坡（0-250 pA/75 ms；图）。

F) from the RMP confirmed a decrease in the rheobase current of the C58/J strain (Rheobase current in C57BL/6J = 153.6 ± 9.5 mV; in C58/J = 125.1 ± 7.4 mV, *p = 0.02; Fig.

F）从RMP证实C58/J菌株的流变基电流降低（C57BL/6J中的流变基电流=153.6±9.5 mV；在C58/J=125.1±7.4 mV时，*p=0.02；图。

G) and latency to fire action potentials (latency in C57BL/6J = 68.9 ± 7.9 ms; in C58/J = 48.1 ± 6.3 ms,*p = 0.04; Fig.

G）以及四种动作电位的潜伏期（C57BL/6J的潜伏期为±68.9±7.9°ms；C58/J的潜伏期==48.1±6.3°ms，*p=0.04；图。

H), supporting the notion of increased excitability of PCs in the C58/J strain.

H），支持C58/J菌株中PC兴奋性增加的观点。

Next, the action potential (AP) kinetics was analyzed. Figure

接下来，分析动作电位（AP）动力学。图

A shows superimposed AP spikes and Fig.

A显示叠加的AP尖峰和图。

B shows the averaged AP phase plots from which the kinetics parameters were obtained. C58/J CA3 PCs exhibited increased AP amplitude compared with control cells (AP amplitude in C57BL/6J = 145.8 ± 2.7 mV; in C58/J = 153.6 ± 1.8 mV, *p = 0.02; Fig.

B显示了获得动力学参数的平均AP相图。与对照细胞相比，C58/J CA3 PC表现出增加的AP幅度（C57BL/6J中的AP幅度=145.8±2.7 mV；；图。

C). Likewise, C58/J CA3 PCs exhibited increased fast afterhyperpolarization (fAHP) amplitude compared with control cells (fAHP in C57BL/6J = − 52.4 ± 0.5 mV; in C58/J = − 49.5 ± 1.1 mV, *p = 0.02; Fig.

C）。同样，与对照细胞相比，C58/J CA3 PC表现出增加的快速超极化后（fAHP）幅度（C57BL/6J中的fAHP）=-52.4±0.5 mV；；图。

D). No statistical difference was found in CA3 PC AP thresholds between groups (Fig.

D）。组间CA3 PC AP阈值无统计学差异（图）。

E).

E）。

Fig. 4

图4

Action potential kinetics of the CA3 pyramidal cells of the C58/J strain. (

C58/J株CA3锥体细胞的动作电位动力学。（笑声）(

) Superimposed AP spikes show the increased fast afterhyperpolarization (fAHP) phase of the action potential in the C58/J CA3 vs. C57BL/6J cells. (

)叠加的AP峰值显示C58/J CA3与C57BL/6J细胞中动作电位的快速超极化后（fAHP）阶段增加。（笑声）(

B类

) Averaged phase plots showing the membrane potential’s dynamical evolution during the action potential. Violin plots contrast the kinetic parameters of the AP obtained from the C57BL/6J and the C58/J strains. (

)平均相图显示了动作电位期间膜电位的动态演变。小提琴图对比了从C57BL/6J和C58/J菌株获得的AP的动力学参数。（笑声）(

C级

) The action potential amplitude and (

)动作电位幅度和(

) the fAHP were increased in the C58/J strain compared to C57BL/6J mice. However, (

)与C57BL/6J小鼠相比，C58/J菌株中的fAHP增加。但是(

) the voltage threshold to elicit an action potential and (

)引发动作电位的电压阈值和(

F级

) the action potential half-duration remained unchanged in both groups. (

)。（笑声）(

克

) The maximal rise slope increased, and the (

)最大上升斜率增加，并且(

小时

) maximal decay slope decreased in the C58/J strain compared with the C57BL/6J strain. n = 16 cells/6 animals in C57BL/6J, n = 17 cells/5 animals in C58/J. Each symbol within the violin plots represents an individual cell’s value. *p < .05; **p < .01. Additional details of statistical analyses are in Supplementary Table .

)与C57BL/6J菌株相比，C58/J菌株的最大衰减斜率降低。C57BL/6J中的n=16个细胞/6只动物，C58/J中的n=17个细胞/5只动物。小提琴图中的每个符号代表单个细胞的值*p<0.05**p<0.01。统计分析的其他细节见补充表。

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Additional kinetic properties were revealed from the phase plot analysis. Compared to the C57BL/6J, the C58/J CA3 PCs showed: a non-significant decrease in the AP half-width (H-W in C57BL/6J = 2.77 ± 0.12 ms; in C58/J = 2.56 ± 0.09 ms, p = 0.2; ns; Fig.

相图分析揭示了其他动力学性质。与C57BL/6J相比，C58/J CA3 PC显示：AP半宽度无显着降低（C57BL/6J中的H-W=2.77±0.12 ms；在C58/J=2.56±0.09 ms，p=0.2；ns；图。

F); increased AP rise slope (max rise slope in C57BL/6J = 162.2 ± 4.9 mV ms

F）；AP上升斜率增加（C57BL/6J的最大上升斜率=162.2±4.9 mV ms

−1

; in C58/J = 183.9 ± 5.8 mV ms

C58/J=183.9±5.8±mV ms

−1

, *p = 0.009; Fig.

，*p=0.009；图。

G) and decreased AP repolarization slope (repolarization slope in C57BL/6J = –57.2 ± 3 mV ms

G）并降低AP复极斜率（C57BL/6J的复极斜率=–57.2±3 mV ms

−1

; in C58/J = − 68.9 mV ms

；在C58/J中=-68.9 mV ms

−1

,*p = 0.01; Fig.

；图。

H). Thus, suggesting altered functionality of K

H）。因此，提示K的功能发生了改变

channels underlying the AP spike in the C58/J strain.

。

Figure

图

A,B show representative AP firing evoked with depolarizing current injections (1 s. duration/300 pA steps), and Fig.

A、 B显示用去极化电流注射诱发的代表性AP放电（1秒持续时间/300 pA步长），以及图。

C,D the raster plots obtained from 14 CA3 PCs contrasting the AP discharge. First, we corroborated our prediction since the AP firing was increased in the C58/J CA3 PCs compared with C57BL/6J cells. The increased AP number of the C58/J neurons is depicted in Fig.

C、 D从14个CA3 PC获得的光栅图对比AP放电。首先，我们证实了我们的预测，因为与C57BL/6J细胞相比，C58/J CA3 PC中的AP放电增加。C58/J神经元的AP数量增加如图所示。

E (*p = 0.04). By computing the slope from the firing frequency curves, we found a significant increase in the neuronal gain of C58/J CA3 PCs (slope in C57BL/6J CA3 PCs = 0.04 ± 0.1 mV ms

E（*p=0.04）。通过从放电频率曲线计算斜率，我们发现C58/J CA3 PC的神经元增益显着增加（C57BL/6J CA3 PC的斜率=0.04±0.1 mV ms

−1

; in C58/J = 0.11 ± 0.05 mV ms

；在C58/J中[UNK]=[UNK]0.11[UNK].±[UNK]1.05[UNK]-mVms

−1

, *p = 0.049; Fig.

，*p=0.049；图。

F). Despite the increased gain of the C58/J CA3 PCs, no difference was found between the time decay of the instantaneous firing frequency in any of the experimental groups (Fig.

F）。尽管C58/J CA3 PC的增益增加，但在任何实验组中，瞬时放电频率的时间衰减之间没有发现差异（图）。

G). Collectively, these data demonstrate that C58/J CA3 PCs exhibit altered K

G）。总的来说，这些数据表明C58/J CA3 PC表现出改变的K

channel functionality, including decreased inward rectification mediated by the K

通道功能，包括由K介导的内向整流减少

红外线

conductance and faster inactivation of the transient fast-inactivating K

瞬时快速失活K的电导和快速失活

conductance underlying the fast repolarization of the AP

AP快速复极的电导

with no changes in the outward K

conductances active near the RMP. Our analysis did not reveal significant changes in Na

RMP附近的电导活跃。我们的分析未发现Na的显着变化

conductances underlying the AP of CA3 PCs.

CA3 PC AP下的电导。

Fig. 5

图5

CA3 pyramidal cells from the C58/J strain exhibit an increased firing rate. (

来自C58/J菌株的CA3锥体细胞表现出增加的放电速率。（笑声）(

B类

) Current clamp recordings show the typical firing response in both experimental conditions. (

)电流钳记录显示了两种实验条件下的典型放电响应。（笑声）(

C,D

C、 D

) Raster plots showing the temporal mapping of action potential firing from 14 cells for each experimental condition. Scatter plots and sigmoid fits summarize the (

)光栅图显示了每个实验条件下从14个细胞发射的动作电位的时间映射。散点图和S形拟合总结了(

) increased action potential discharge (

)动作电位放电增加(

F级

) firing frequency. Inset gain values were computed from each experimental condition (

)点火频率。从每个实验条件计算插入增益值(

克

) Scatter plot—instantaneous firing frequency as a function of the number of action potentials. No statistical difference was found in the firing frequency between experimental groups. n = 6 animals in C57BL/6J; n = 5 animals in C58/J. Each symbol within the scatter plots represents the group mean ± S.E.M.

)散点图瞬时放电频率与动作电位数量的函数关系。实验组之间的放电频率没有统计学差异。C57BL/6J中的n=6只动物；C58/J中的n=5只动物。散点图中的每个符号代表组平均值±S.E.M。

Additional details of statistical analyses are in Supplementary Table .

统计分析的其他详细信息见补充表。

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C58/J strain exhibits dysregulated synaptic transmission at the mossy fiber (MF)–CA3 synapse

C58/J菌株在苔藓纤维（MF）-CA3突触处表现出突触传递失调

Following the experimental manipulations in the acute hippocampal slice, we next characterized the synaptic strength and synaptic plasticity profile of the mossy fiber (MF) to CA3 PCs synapse (MF–CA3) in the C58/J strain. For these experiments, we switched to extracellular recordings to analyze a larger number of MF–CA3 synapses over an extended period of time (see Fig. .

在急性海马切片中进行实验操作后，我们接下来表征了C58/J菌株中苔藓纤维（MF）到CA3 PCs突触（MF–CA3）的突触强度和突触可塑性。对于这些实验，我们切换到细胞外记录，以分析更长时间内大量的MF–CA3突触（见图）。

B for stimulation electrode and the recording pipette placement used for extracellular recordings). We first determined the synaptic strength of the MF-evoked field excitatory postsynaptic potentials (MF fEPSP) via an input–output (I–O) relationship in the C58/J and C57BL/6J strains.

B用于刺激电极和用于细胞外记录的记录移液管放置）。我们首先通过C58/J和C57BL/6J菌株中的输入-输出（I-O）关系确定了MF诱发的场兴奋性突触后电位（MF-fEPSP）的突触强度。

In response to increasing current pulses (0–400 µA, 100 µs duration), the C57BL/6J hippocampal slices exhibited a sustained increase in MF fEPSP amplitude, reaching a maximal value of 5.64 ± 0.48 mV. However, MF fEPSPs from the C58/J slices exhibited a smaller response, reaching a maximal amplitude of 3.84 ± 0.3 mV (*p = 0.031; Fig. .

。然而，来自C58/J切片的MF-fEPSP表现出较小的响应，达到最大振幅3.84±0.3 mV（*p=0.031；图。

A; representative traces are depicted in the upper insert), indicating decreased strength of the glutamatergic transmission in the C58/J strain.

A、代表性的痕迹描绘在上部插入物中），表明C58/J菌株中谷氨酸能传递的强度降低。

Fig. 6

图6

MF-CA3 synapses from C58/J mice exhibit decreased synaptic transmission. (

来自C58/J小鼠的MF-CA3突触表现出突触传递减少。（笑声）(

) I–O relationships from C57BL/6J and C58/J mice. Slices from C58/J mice exhibited decreased mossy fiber-mediated fEPSPs amplitudes compared with the C57BL/6J mice. Upper panels, representative MF fEPSPs from both experimental groups. n = 7 slices/6 animals in C57BL/6J; n = 7 slices/5 animals in C58/J.

)C57BL/6J和C58/J小鼠的I-O关系。与C57BL/6J小鼠相比，来自C58/J小鼠的切片表现出苔藓纤维介导的fEPSP振幅降低。上图，来自两个实验组的代表性MF-fEPSP。C57BL/6J中的7片/6只动物；在C58/J中n=7片/5只动物。

B类

) Scatter plot and linear regression from the fiber volley (FV) amplitude vs. current intensity relationship. The mean slope was similar between both groups. n = 7 slices/6 animals in C57BL/6J; n = 7 slices/5 animals in C58/J. (

)纤维凌空（FV）振幅与电流强度关系的散点图和线性回归。两组之间的平均斜率相似。C57BL/6J中的7片/6只动物；在C58/J中n=7片/5只动物(

C级

) Pearson correlation analysis between MF fEPSP amplitude and FV amplitude. The values were obtained from the I-O relationship. Slices from C57BL/6J exhibited a high correlation (r = 0.92), and slices from C58/J exhibited a moderate correlation (r = 0.61). (

)MF-fEPSP振幅与FV振幅之间的Pearson相关分析。这些值是从I-O关系中获得的。来自C57BL/6J的切片表现出高度相关性（r=0.92），来自C58/J的切片表现出中等相关性（r=0.61）(

) Representative MF fEPSP trace depicting the kinetic parameters measured. The violin plots show that there were no significant differences between (

)代表性的MF-fEPSP迹线描绘了测量的动力学参数。小提琴图显示，两者之间没有显着差异(

) peak latency (

)峰值延迟(

F级

) and MF fEPSP half-width. (

)和MF-fEPSP半宽。（笑声）(

克

) Violin plots showing the decay time of the MF fEPSP in both experimental groups. n = 9 slices/6 animals in C57BL/6J; n = 10 slices/5 animals in C58/J. (

)小提琴图显示了两个实验组中MF-fEPSP的衰减时间。C57BL/6J中的n=9片/6只动物；在C58/J中n=10片/5只动物(

小时

) Representative traces of MF fEPSPs evoked with paired-pulse stimulation at 60 ms for slices from C57BL/6J mice (black trace) and C58/J mice (red trace). The perfusion of DCG-IV (5 µM) confirmed the presynaptic origin of the MF fEPSPs. (

)对于来自C57BL/6J小鼠（黑色迹线）和C58/J小鼠（红色迹线）的切片，在60 ms时通过成对脉冲刺激诱发的MF-fEPSP的代表性迹线。DCG-IV（5µM）的灌注证实了MF-fEPSP的突触前起源。（笑声）(

我

) Time-course graph of MF PPF elicited at increasing ISIs. n = 6 slices/5 animals in C57BL/6J, n = 8 slices/5 animals in C58/J. Inset violin plot MF PPF with an ISI of 40 ms showed a significant reduction. Each symbol within the violin and scatter plots represents an individual cell’s value, or the group mean ± S.E.M, respectively.

)。C57BL/6J中的n=6片/5只动物，C58/J中的n=8片/5只动物。ISI为40 ms的插图小提琴图MF PPF显示出显着降低。小提琴和散点图中的每个符号分别代表单个细胞的值或组平均值±s.E.M。

*p < 0.05. Additional details of statistical analyses are in Supplementary Table .

*p<0.05。统计分析的其他细节见补充表。

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Next, we examined the strength of the transference of presynaptic action potentials (fiber volleys, FV) propagating via the MF bundle. For this, we plotted the FV amplitude vs current injection. Then, a linear regression was adjusted to the resulting scatter plot. Although the adjustment of the C58/J strain exhibited a decreased slope steepness compared to the C57BL/6J strain, the difference did not reach statistical significance (Fig. .

接下来，我们检查了通过MF束传播的突触前动作电位（纤维凌空，FV）的转移强度。。然后，将线性回归调整为所得散点图。尽管与C57BL/6J菌株相比，C58/J菌株的调整表现出降低的斜率，但差异没有达到统计学意义（图）。

B). Next, we calculated the correlation between FV and MF fEPSP amplitude. As FV amplitude increases, the resulting MF EPSP is expected to increase linearly

B）。接下来，我们计算了FV和MF-fEPSP幅度之间的相关性。

. Contrary to this prediction, the C58/J slices exhibited an increased slope steepness compared with the C57BL/6J slices (C58/J, r = 0.61; C57BL/6J, r = 0.92; Fig.

与此预测相反，与C57BL/6J切片（C58/J，r = 0.61; C57BL/6J，r=0.92；图。

C). Next, the MF EPSP kinetics was analyzed (Fig.

C）。接下来，分析了MF-EPSP动力学（图）。

D). Neither the MF fEPSP peak latency nor the MF fEPSP half-width was altered in the C58/J slices compared with C57BL/6J slices (Fig.

D）。与C57BL/6J切片相比，C58/J切片中的MF-fEPSP峰值潜伏期和MF-fEPSP半宽度均未改变（图）。

E,F). On the contrary, the MF fEPSP decay time was increased in the C58/J slices (MF decay time in C57BL/6J = 2.11 ± 0.17; in C58/J = 2.67 ± 0.02 ms, *p = 0.045; Fig.

E、。相反，C58/J切片中的MF-fEPSP衰减时间增加（C57BL/6J中的MF衰减时间=2.11±0.17；在C58/J中，=2.67±0.02 ms，*p=0.045；图。

G). These results suggest that the glutamatergic receptors expressed in the C58/J strain differ from those of the C57BL/6J strain, a phenomenon that may affect the induction of synaptic plasticity at the MF—CA3 synapse.

G）。这些结果表明，C58/J菌株中表达的谷氨酸能受体不同于C57BL/6J菌株，这种现象可能影响MF-CA3突触突触可塑性的诱导。

The MF–CA3 synapse is well known for its prominent MF-mediated paired-pulse facilitation (MF PPF) elicited within the milliseconds range

MF-CA3突触以其在毫秒范围内引起的突出的MF介导的成对脉冲促进（MF-PPF）而闻名

. In response to paired-pulse stimulation (inter-stimuli interval [ISI] = 60 ms), slices from both strains exhibited robust MF PPF (Fig.

响应成对脉冲刺激（刺激间隔[ISI]=60 ms），两种菌株的切片均表现出强大的MF PPF（图）。

H). The MF origin of the evoked responses was corroborated via perfusion of the mGluR2 agonist, DCG-IV (5 µM) (Superimposed gray traces in Fig.

H）。诱发反应的MF起源通过灌注mGluR2激动剂DCG-IV（5μM）（图中叠加的灰色痕迹）得到证实。

H). The pharmacological sensitivity to DCG-IV was similar in both experimental groups. Next, we delivered paired pulses using an extended ISI range to further explore the MF PPF in the C58/J strain (ISI = 40, 60, 100, 200, and 500 ms). As illustrated in the time-course graph in Fig.

H）。两个实验组对DCG-IV的药理学敏感性相似。接下来，我们使用扩展的ISI范围提供成对脉冲，以进一步探索C58/J菌株（ISI）中的MF PPF = 40, 60100200和500毫秒）。如图中的时间过程图所示。

I, the MF PPF values were similar at the ISIs from 60 to 500 ms in both groups. Contrary to these findings, we found that MF PPF elicited with 40 ms ISI exhibits a slight reduction in the MF PPF of the C58/J strain (MF PPF in C57BL/6J = 1.8 ± 0.04; in C58/J = 1.63 ± 0.05, *p = 0.021; inset violin plot in Fig. .

一、两组在60至500 ms的ISIs处的MF PPF值相似。与这些发现相反，我们发现用40-ms ISI引发的MF-PPF显示C58/J菌株的MF-PPF略有降低（C57BL/6J中的MF-PPF=1.8±0.04；在C58/J=1.63±0.05中*p=0.021；插图小提琴图。

I). Collectively, these results suggest a desynchronization between presynaptic action potentials and glutamate release that negatively affects the strength of the glutamatergic transmission at the MF–CA3 synapse.

一）。总的来说，这些结果表明，突触前动作电位与谷氨酸释放之间的不同步会对MF-CA3突触的谷氨酸能传递强度产生负面影响。

C58/J strain exhibits decreased NMDAR-independent synaptic potentiation at the MF–CA3 synapse

Our in silico analyses and the cLTP obtained in the synaptosomes suggest a dysregulation of AMPARs on the C58/J strain. Likewise, the extracellular recordings on acute brain slices corroborated altered glutamatergic transmission at the MF–CA3 synapse. The next experiments explored the MF-mediated LTP (MF LTP) on the C58/J strain, a presynaptic form of LTP that requires AMPARs.

我们的计算机分析和在突触体中获得的cLTP表明C58/J菌株上AMPAR失调。同样，急性脑切片上的细胞外记录证实了MF-CA3突触中谷氨酸能传递的改变。接下来的实验探索了C58/J菌株上MF介导的LTP（MF-LTP），这是一种需要AMPAR的突触前形式的LTP。

To isolate the AMPAR-mediated response of the MF–CA3 synapse, 50 µM DL-AP5 + 25 µM of picrotoxin were included in the perfusion bath. Then, a baseline response of MF fEPSP was acquired for 25 min, followed by the delivery of high-frequency stimulation (HFS) to the MF bundle, and the synaptic responses were recorded for an additional 90 min.

为了分离AMPAR介导的MF-CA3突触反应，灌注浴中包括50µM DL-AP5++25µM印防己毒素。。

In response to HFS, slices from C58/J and C57BL/6J exhibited a robust post-tetanic potentiation (PTP) (PTP in C57BL/6J = 205.8 ± 17.55% of baseline response; in C58/J = 187.5 ± 21.29%; see Fig. .

响应HFS，来自C58/J和C57BL/6J的切片表现出强大的强直后增强（PTP）（C57BL/6J中的PTP=基线反应的205.8±17.55%；C58/J=187.5±21.29%；。

A–C). After PTP, a stable potentiation of the MF fEPSP was observed in the C57BL/6J slices that lasted up to 90 min. Contrary to this finding, in the C58/J slices, the MF fEPSP returned to baseline values at this same time point and exhibited reduced synaptic potentiation (MF fEPSP at 90 min post-HFS in C57BL/6J = 176.3 ± 11.66% of baseline value; in C58/J = 146.3 ± 11.66% of baseline,*p = 0.0426; Fig. .

A–C）。PTP后，在C57BL/6J切片中观察到MF-fEPSP的稳定增强，持续长达90分钟。与此发现相反，在C58/J切片中，MF-fEPSP在同一时间点恢复到基线值，并表现出降低的突触增强作用（在C57BL/6J中HFS后90分钟的MF-fEPSP=基线值的176.3±11.66%；在C58/J=146.3±11.66%的基线中，*p=0.0426；图。

A–C). The decreased MF LTP magnitude in slices from C58/J is individually depicted in the heatmap in Fig.

A–C）。来自C58/J的切片中降低的MF LTP幅度在Fig.的热图中单独描绘。

D. Likewise, by plotting the cumulative probability distribution of the synaptic potentiation, we show that slices from C58/J exhibit decreased MF LTP compared to slices from C57BL/6J (*p < 0.05; Fig.

D、同样，通过绘制突触增强的累积概率分布，我们表明，与C57BL/6J切片相比，C58/J切片的MF LTP降低（*p < 0.05; 图。

E). These experiments demonstrate that presynaptic potentiation at the MF-CA3 synapse of the hippocampus is weaker in the C58/J strain compared to C57BL/6J.

E）。这些实验表明，与C57BL/6J相比，C58/J菌株中海马MF-CA3突触的突触前增强作用较弱。

Fig. 7

图7

MF–CA3 synapses from C58/J mice exhibit weakened NMDA receptor-independent LTP. (

来自C58/J小鼠的MF-CA3突触表现出减弱的NMDA受体非依赖性LTP。（笑声）(

) Representative MF fEPSP acquired during baseline (1), PTP (2), 90 min post-HFS (3) and during perfusion of DCG-IV (4) in C57BL/6J (black traces) and C58/J (red traces) mice. Traces in solid color (black or red) represent the mean fEPSP of 10 consecutive sweeps. (

)在基线（1），PTP（2），HFS后90分钟（3）和在C57BL/6J（黑色痕迹）和C58/J（红色痕迹）小鼠中灌注DCG-IV（4）期间获得的代表性MF-fEPSP。纯色（黑色或红色）的痕迹表示连续10次扫描的平均fEPSP。（笑声）(

B类

) Time-course graph of MF LTP induced by high-frequency stimulation (HFS). Tetanic stimulation induced a robust increase in the MF fEPSP slope up to 90 min. (

)高频刺激（HFS）诱导的MF LTP的时程图。强直性刺激导致MF-fEPSP斜率强烈增加至90分钟。（笑声）(

C级

) Bar graphs summarizing the MF fEPSP slope (% baseline) during PTP, 90 min post-HFS, and DCG-IV (

)条形图总结了PTP期间，HFS后90分钟和DCG-IV期间的MF-fEPSP斜率（%基线）(

) Heatmap depicts the magnitude of LTP (%) in each slice by group. (

)热图按组描绘了每个切片中LTP（%）的大小。（笑声）(

) Cumulative probability plot of synaptic potentiation. The leftward shift of the synaptic responses from C58/J slices (red line) indicates decreased synaptic potentiation. n = 6 slices/6 animals in C57BL/6J; n = 8 slices/5 animals in C58/J. Each symbol within the time-course graph and the bar plots represents the group mean ± S.E.M, or an individual animal, respectively.

)突触增强的累积概率图。C58/J切片（红线）的突触反应向左移动表明突触增强作用降低。C57BL/6J中的n=6片/6只动物；C58/J中的n=8片/5只动物。时程图和条形图中的每个符号分别代表组平均值±S.E.M或单个动物。

*p < 0.05. Additional details of statistical analyses are in Supplementary Table .

*p<0.05。统计分析的其他细节见补充表。

S2级

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C58/J mice exhibit hyperactivity and potential changes in memory

C58/J小鼠表现出多动症和潜在的记忆变化

We then investigated whether the C58/J strain exhibited alterations in the memory process based on the previously identified changes in the electrophysiological properties of the hippocampal circuit.

然后，我们根据先前确定的海马回路电生理特性的变化，研究了C58/J菌株是否在记忆过程中表现出改变。

In previous behavioral evaluations, the C58/J strain demonstrated locomotor hyperactivity

在先前的行为评估中，C58/J菌株表现出运动过度活跃

. Therefore, before assessing performance in memory tests, we evaluated locomotor behavior in the open field test in both strains (see the Methods section for detailed analysis procedures). We found that the total number of line crossings in the arena was significantly higher in C58/J mice compared to the C57BL/6J strain (# of crossings in C57BL/6J = 126.0 ± 31.46; in C58/J = 277.0 ± 85.25, *p = 0.0012, Fig. .

因此，在评估记忆测试的表现之前，我们评估了两种菌株在野外测试中的运动行为（有关详细的分析程序，请参见“方法”部分）。我们发现，与C57BL/6J菌株相比，C58/J小鼠的竞技场中的线交叉总数显着更高（C57BL/6J中的交叉数=126.0±31.46；在C58/J=277.0±85.25中*p=0.0012，图。

A). Additionally, we observed that the increased exploratory behavior in C58/J mice occurred in both the peripheral and central zones of the arena compared to the control strain (# of peripheral line crossings in C57BL/6J = 96.50 ± 19.75; in C58/J = 217.4 ± 72.80, *p = 0.0019, Fig.

A）。此外，我们观察到，与对照菌株相比，C58/J小鼠的探索行为增加发生在竞技场的外围和中央区域（C57BL/6J中的外围线交叉=96.50±19.75；在C58/J=217.4±72.80中*p=0.0019，图。

B; # of central line crossings in C57BL/6J = 29.50 ± 13.49; in C58/J = 59.63 ± 20.13, *p = 0.0034, Fig.

B、 C57BL/6J中心线交叉口=29.50±13.49；在C58/J=59.63±20.13中*p=0.0034，图。

C) thus confirming increased general locomotion.

C）从而证实了一般运动的增加。

Fig. 8

图8

The C58/J strain exhibits hyperactivity and potential changes in memory. Locomotion was assessed through the open field test in both the C57BL/6J and the C58/J strain. Violin plots summarize the total number of crossings across the arena (

C58/J菌株表现出多动症和潜在的记忆变化。通过C57BL/6J和C58/J菌株的旷场测试评估运动。小提琴情节总结了整个竞技场的穿越总数(

) and the number of crossings in the peripheral and (

)以及外围和(

B类

) central zones of the arena (

)竞技场中心区域(

C级

) in both strains. Memory performance in both the C57BL/6J and the C58/J strains was assessed using the novel object recognition test (NOR) and the contextual fear conditioning task. Violin plots summarize the exploration index (EI) for identical objects in the acquisition phase (

)在两种菌株中。使用新物体识别测试（NOR）和情境恐惧调节任务评估C57BL/6J和C58/J菌株的记忆表现。小提琴图总结了采集阶段相同物体的探索指数（EI）(

), and the discrimination index (DI) for novel objects (NO) in both strains during the short-term (

)，以及短期内两种菌株中新物体（NO）的辨别指数（DI）(

) and long-term (

)和长期(

F级

) memory trials. (

)记忆试验。（笑声）(

克

) The time curve summarizes the percentage of immobilization/freezing on days 1 and 2 (acquisition phase) and on day 3 (memory trial) in the contextual fear memory task in both strains. n = 8 animals in both strains. Each symbol within the time curve and the violin plots represents the group mean ± S.D., or an individual animal respectively.

)时间曲线总结了两种菌株在情境恐惧记忆任务中第1天和第2天（采集阶段）以及第3天（记忆试验）的固定/冻结百分比。两种菌株中的n=8只动物。时间曲线和小提琴图中的每个符号分别代表组平均值±S.D.或个体动物。

*p < 0.05. Additional details of statistical analyses are in Supplementary Table S2..

*p<0.05。统计分析的其他细节见补充表S2。。

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Subsequently, we conducted the novel object recognition test (NOR) to assess hippocampus-related short-term and long-term memory

随后，我们进行了新物体识别测试（NOR），以评估海马相关的短期和长期记忆

. During the acquisition phase, both strains demonstrated a similar exploration index (EI) for two identical objects, which were later designated as familiar objects (FO) in subsequent trials, indicating no bias toward either object between the strains (C57BL/6J Object 1 = 46.74 ± 8.57%, in C58/J Object 1 = 49.45 ± 6.79%; C57BL/6J Object 2 = 53.26 ± 8.57%; in C58/J Object 2 = 50.55 ± 6.79%, p = 0.7381, ns, Fig. .

在采集阶段，两个菌株对两个相同的物体表现出相似的探索指数（EI），后来在随后的试验中被指定为熟悉物体（FO），表明菌株之间对任何一个物体都没有偏见（C57BL/6J物体1）=46.74±8.57%，在C58/J对象中，1=49.45±6.79%；C57BL/6J对象2=53.26±8.57%；在C58/J对象2中，2=50.55±6.79%，p=0.7381，ns，图。

D). In the short-term and long-term memory trials, we did not observe differences in the discrimination index (DI) for the novel object (NO) in C58/J mice compared to the control strain (Short-term: C57BL/6J: 24.12 ± 20.42%; in C58/J: 9.81 ± 22.23%, p = 0.2014, ns; Long-term: C57BL/6J: 24.11 ± 32.73%; in C58/J: 16.52 ± 33.62%, p = 0.6545, ns, Fig. .

D）。在短期和长期记忆试验中，我们没有观察到C58/J小鼠与对照品系（短期：C57BL/6J：24.12±20.42%；在C58/J中：9.81±22.23%，2014年，ns；长期：C57BL/6J：24.11±32.73%；在C58/J中：16.52±33.62%，p=0.6545，ns，图。

E,F). These results suggest comparable levels of NO preference between the strains and no significant differences in memory recognition in C58/J mice.

E、。这些结果表明，菌株之间没有相似的偏好水平，C58/J小鼠的记忆识别没有显着差异。

Then, we assessed contextual memory associated with the CA3 region of the dorsal hippocampus through the contextual fear conditioning task

然后，我们通过情境恐惧条件任务评估了与背侧海马CA3区相关的情境记忆

. We did not find significant differences in the percentage of freezing/immobilization displayed during the acquisition phase on Days 1 and 2 between the two strains (C57BL/6J Day 1 = 5.03 ± 1.34%, C58/J Day 1 = 6.05 ± 5.0%, p = 0.9322, ns; C57BL/6J Day 2 = 15.35 ± 12.41%, C58/J Day 2 = 4.58 ± 0.81%, p = 0.1260, ns, Fig. .

我们没有发现两种菌株在第1天和第2天采集阶段显示的冷冻/固定百分比有显着差异（C57BL/6J第1天=5.03±1.34%，C58/J第1天=6.05±5.0%，p=0.9322，ns；C57BL/6J第2天=15.35±12.41%，C58/J第2天=4.58±0.81%，p=0.1260，ns，图。

G). Additionally, there were no significant differences in the time spent moving on Days 1 and 2 between the two strains (C57BL/6J Day 1 = 170.90 ± 2.41 s, in C58/J Day 1 = 169.10 ± 9.00 s, p = 0.9322, ns; C57BL/6J Day 2 = 152.40 ± 22.33 s, in C58/J Day 2 = 171.80 ± 1.45 s, p = 0.1260, ns, Supplementary Fig.

G此外，在第1天和第2天，两种菌株1260 ns的移动时间没有显著差异，补充图。

S3级

). In contrast, during the memory trial, the C57BL/6J strain exhibited increased freezing/immobilization compared to the C58/J mice (Interaction Day-Strain: *p = 0.0223; Factor Day: p = 0.0585, ns; Factor Strain: *p = 0.0016; C57BL/6J Day 3 = 18.69 ± 10.99%, C58/J Day 3 = 5.34 ± 2.40%, *p = 0.0315, Fig. .

)。相反，在记忆试验期间，与C58/J小鼠相比，C57BL/6J菌株表现出增加的冷冻/固定作用（相互作用日菌株：*p = 0.0223; ，ns；因子应变：*p=0.0016；C57BL/6J第3天=18.69±10.99%，C58/J第3天=5.34±2.40%*p=0.0315，图。

G), which, in turn, spent more time moving around the cage (C57BL/6J Day 3 = 146.40 ± 19.78 s, C58/J Day 3 = 170.40 ± 4.33 s, *p = 0.0315, Supplementary Fig.

G），这反过来又花费了更多的时间在笼子周围移动（C57BL/6J第3天弯曲146.40次，C58/J第3天弯折170.40±4.33秒，*p弯曲=0.0315，补充图。

). This result shows that contextual fear memory is clearly preserved in C57BL/6J mice, but may not be the case for C58/J mice.

)。该结果表明，情境恐惧记忆在C57BL/6J小鼠中得到了明显的保留，但C58/J小鼠可能并非如此。

Discussion

讨论

We have previously described several genetic and morphological alterations in the hippocampus of the C58/J strain, including polymorphisms in genes that regulate neurogenesis, as well as alterations in the complexity of dendritic arborization, the shape of dendritic spines in pyramidal cells, and abnormalities in the proliferation and maturation trajectory of newborn DG granule cells.

我们之前已经描述了C58/J菌株海马中的几种遗传和形态学改变，包括调节神经发生的基因多态性，以及树突树枝化的复杂性，锥体细胞中树突棘的形状以及异常的改变新生DG颗粒细胞的增殖和成熟轨迹。

. C57BL/6J mice have served as a control group in previous studies, as well as in the present one, as they share a common ancestry with C58/J mice but do not display the alterations associated with an autistic phenotype, as the C58J strain does

C57BL/6J小鼠在先前的研究以及本研究中均作为对照组，因为它们与C58/J小鼠具有共同的血统，但不像C58J菌株那样表现出与自闭症表型相关的改变

Previous studies have also documented several ASD-related electrophysiological alterations affecting the kinetics of several K

先前的研究还记录了几种与ASD相关的电生理改变，这些改变影响了几种K的动力学

currents, the AP discharge, and the strength of glutamatergic transmission

电流，AP放电和谷氨酸能传递的强度

. Together, these results and our current findings support the notion that the transcriptomic imbalances in the C58/J strain alter the intrinsic excitability, synaptic transmission, and plasticity of the synapses formed by the axons of the dentate granule cells, the mossy fibers with CA3 PCs. Consequently, these dysregulations may hinder the performance in memory tasks in which area CA3 takes part..

总之，这些结果和我们目前的发现支持这样的观点，即C58/J菌株中的转录组失衡改变了齿状颗粒细胞轴突形成的突触的内在兴奋性，突触传递和可塑性，这些突触是由CA3 PC形成的苔藓纤维。因此，这些失调可能会阻碍CA3参与的记忆任务的表现。。

Our in silico analysis aimed to detect genes carrying Cn SNPs responsible for changes in the amino acid sequence of encoded proteins, which could potentially affect their structure and functionality

我们的计算机分析旨在检测携带Cn SNP的基因，这些基因负责编码蛋白质氨基酸序列的变化，这可能会影响其结构和功能

. Our results revealed alterations in

。我们的结果显示

Disc1

and

和

Map1a

地图1A

, which are critical for neurogenesis and structural plasticity

，这对神经发生和结构可塑性至关重要

. Also, the proteins encoded by

此外，由

Disc1

and

和

Map1a

地图1A

regulate the electrophysiological properties of hippocampal PCs. In this sense, mutations in

调节海马PC的电生理特性。从这个意义上讲，突变

Disc1

stimulate an early onset of anomalous bursting of CA1 PCs and alter, in an input-specific fashion, the induction of LTP in the hippocampus

刺激CA1 PC异常爆发的早期发作，并以特定于输入的方式改变海马中LTP的诱导

. Meanwhile, mice lacking the

同时，缺乏

Map1a

地图1A

gene display altered amplitude and frequency of NMDA-mediated EPSCs and exhibit reduced synaptic plasticity (LTP and LTD)

基因显示改变了NMDA介导的EPSC的幅度和频率，并表现出突触可塑性降低（LTP和LTD）

Our GO enrichment analysis revealed alterations in a series of biochemical elements responsible for excitability, synaptic transmission, and plasticity

我们的GO富集分析揭示了一系列负责兴奋性、突触传递和可塑性的生化元素的改变

. Remarkably, the altered biochemical elements reported in this study are involved in the atypical neuronal communication associated with ASD

值得注意的是，这项研究中报道的改变的生化元素与ASD相关的非典型神经元通讯有关

. We found the presence of 13 genes with Cn SNPs associated with autistic behavior, according to the term established by the Human Phenotype Ontology, and seven genes with Cn SNPs orthologous to human genes implicated in ASD etiology (

根据人类表型本体论建立的术语，我们发现存在13个与自闭症行为相关的Cn SNP基因，以及7个与ASD病因有关的人类基因同源的Cn SNP基因(

ANK2, ASXL3, MYT1L, NF1, NRXN3, SCN2A,

ANK2，ASXL3，MYT1L，NF1，NRXN3，SCN2A，

and

和

SHANK2

SHANK2型

), as documented in the SFARI GENE database. Consistent with these findings, a gain-of-function mutation in the

)，如SFARI基因数据库中所述。与这些发现一致的是，在

Scn2a

gene, which encodes the voltage-gated Na

编码电压门控Na的基因

channels, results in hyperexcitability of hippocampal neurons and increases the after-discharge of population spikes following tetanic stimulation, suggesting hypersensitivity to external inputs

通道，导致海马神经元过度兴奋，并增加强直刺激后群体尖峰的放电后，提示对外部输入过敏

. Other studies in brain slices and human-derived iPSCS reported that

大脑切片和人类来源的iPSC的其他研究报道

MYT1L

haploinsufficiency results in spontaneous neuronal network activity and increased spontaneous EPSCs of CA1 PCs

单倍剂量不足会导致CA1 PC的自发性神经元网络活动和自发性EPSC增加

, whereas loss-of-function mutations in the

，而功能丧失突变

SHANK2

SHANK2型

gene result in altered morphology of hippocampal neurons and increased somatic excitability

该基因导致海马神经元形态改变和体细胞兴奋性增加

, suggesting a link between polymorphisms, abnormal neuronal activity, and autistic-like behaviors.

，表明多态性，异常神经元活动和自闭症样行为之间存在联系。

Consistent with these findings, our patch-clamp recordings showed altered K + conductances, including the BaCl2-sensitive Kir

与这些发现一致，我们的膜片钳记录显示K++电导发生了改变，包括对BaCl2敏感的Kir

, and the delayed K + conductances that set the rheobase to elicit an AP. Several SNPs encoding Kir channels are present in ASD individuals and animal models of autism, including the

，以及延迟的K++电导，这些电导设置了流变酶以引发AP。自闭症个体和自闭症动物模型中存在几种编码Kir通道的SNP，包括

KCNJ10

gene

基因

, which was also found in our study. In line with this, we also observed increased fast-inactivating K⁺ conductance (fast AHP) modulated by A-type K⁺ channels, an ionic mechanism that exacerbates neuronal hyperexcitability. Previous studies demonstrated that synaptic potentiation is restored by decreasing the A-type K⁺ activity in a model of Fragile X syndrome.

，这也在我们的研究中发现。与此相一致，我们还观察到由A型K+通道调节的快速失活K+电导（快速AHP）增加，这是一种加剧神经元过度兴奋的离子机制。先前的研究表明，在脆性X综合征模型中，通过降低A型K+活性可以恢复突触增强。

. Our data suggests that the increased excitability of CA3 PCs in the C58/J strain can be partially ascribed to the altered functionality of Kir and A-type K channels. Consistent with this tenet, we found polymorphisms in five genes that encode K

我们的数据表明，C58/J菌株中CA3 PC的兴奋性增加可部分归因于Kir和A型K通道功能的改变。与这一原则一致，我们在五个编码K的基因中发现了多态性

channels to support this possibility (

支持这种可能性的渠道(

Kcnj10, Kcns3, Kcnj14, Kcnk15, and Kcnh1

Kcnj10、Kcns3、Kcnj14、Kcnk15和Kcnh1

Likewise, according to our in silico predictions, the C58/J strain may exhibit changes that alter the synaptic strengthening and plasticity capabilities of the glutamatergic synapses. Consistent with this tenet, our results show altered expression of the GluA1 subunit of AMPAR and presynaptic Nrnx1β in the membrane of hippocampal synaptosomes of the C58/J strain which impairs the expression of cLTP, a plasticity form dependent on NMDA receptors, similar to that observed at Schaffer collateral-CA1 synapses.

同样，根据我们的计算机模拟预测，C58/J菌株可能表现出改变谷氨酸能突触的突触强化和可塑性能力的变化。与此原理一致，我们的结果显示AMPAR的GluA1亚基和突触前Nrnx1β在C58/J菌株的海马突触体膜中的表达改变，这损害了cLTP的表达，cLTP是一种依赖于NMDA受体的可塑性形式，类似于在Schaffer侧支CA1突触中观察到的。

. We also found decreased strength of the synaptic transmission at the presynaptic and postsynaptic loci of the MF–CA3 synapse. This is a relevant finding since it is well-known that AMPA receptors mediate glutamatergic transmission and MF LTP at the MF—CA3 synapse

我们还发现MF–CA3突触的突触前和突触后位点的突触传递强度降低。这是一个相关的发现，因为众所周知，AMPA受体介导MF-CA3突触的谷氨酸能传递和MF-LTP

. Moreover, we demonstrate that induction of MF LTP with HFS on acute hippocampal slices triggers a blunted MF LTP.

此外，我们证明在急性海马切片上用HFS诱导MF-LTP会触发MF-LTP钝化。

The underlying mechanisms of these phenomena may involve synaptic genes with Cn SNPs identified in C58/J mice. For example, NRXN3 and SHANK2 proteins (encoded by the

这些现象的潜在机制可能涉及在C58/J小鼠中鉴定出具有Cn SNP的突触基因。例如，NRXN3和SHANK2蛋白（由

Nrxn3

and

和

Shank2

Shank2型

genes, respectively) may contribute to decreased synaptic strength by reducing presynaptic release and altering the expression of the GluA2 subunit of AMPAR

基因）可能通过减少突触前释放和改变AMPAR GluA2亚基的表达来降低突触强度

. Additionally, SHANK2 supports GluA1 trafficking to the synapse and acts as a scaffold for synaptic proteins during cLTP

此外，SHANK2支持GluA1向突触的运输，并在cLTP期间充当突触蛋白的支架

. The NRXN3 protein is also essential for MF LTP expression through its interaction with the synaptic organizer C1ql2

NRXN3蛋白通过与突触组织者C1ql2的相互作用，对MF LTP的表达也至关重要

. Moreover, the ubiquitin-protein ligase E3 component encoded by the

此外，泛素蛋白连接酶E3成分由

Ubr1

gene could play a role in GluA1 ubiquitination, which is crucial for AMPAR endocytosis and synaptic plasticity regulation

该基因可能在GluA1泛素化中发挥作用，这对于AMPAR内吞作用和突触可塑性调节至关重要

. The CNTNAP2 protein, encoded by the

。CNTNAP2蛋白，由

Cntnap2

CNTNAP2

gene, is upregulated in cLTP and plays a key role in calcium dynamics

基因在cLTP中上调，在钙动力学中起关键作用

These results strongly suggest that Cn SNPs are related to modifications in synaptic features of the hippocampus, affecting both NMDA receptor-dependent and -independent plasticity forms. However, further research is needed to investigate the specific roles of these genes. Additionally, the trafficking of AMPAR subtypes, such as GluA2-containing AMPARs, should be further assessed due to their distinct functional properties.

。然而，需要进一步的研究来调查这些基因的具体作用。此外，由于其独特的功能特性，应进一步评估AMPAR亚型（例如含GluA2的AMPAR）的贩运。

, as this study focused only on GluA1-containing AMPARs.

，因为这项研究仅关注含有GluA1的AMPAR。

The neuronal network contained in area CA3 of the hippocampus, including the synapse formed by MF–CA3, is critical for spatial and contextual memory encoding

海马CA3区包含的神经元网络，包括MF-CA3形成的突触，对于空间和情境记忆编码至关重要

, whereas the integrity of CA3–CA1 synapses is necessary for the consolidation of object recognition memory

，而CA3-CA1突触的完整性对于巩固物体识别记忆是必要的

. Furthermore, the exploration of novel objects promotes the induction of LTP-like enhancement of CA3–CA1 synaptic strength, indicating that CA3 synaptic modulation and plasticity are essential for novelty recognition memory

此外，对新物体的探索促进了CA3-CA1突触强度的LTP样增强的诱导，表明CA3突触调节和可塑性对于新颖性识别记忆至关重要

As a further step in this study, we evaluated recognition and contextual memory using the novel object recognition (NOR) test and the contextual fear memory task.

作为本研究的进一步步骤，我们使用新物体识别（NOR）测试和情境恐惧记忆任务评估了识别和情境记忆。

The discrimination index (DI) in the NOR test is a relative measure of memory performance, indicating whether mice prefer exploring a novel object (NO) over a familiar one (FO)

NOR测试中的辨别指数（DI）是记忆表现的相对量度，表明小鼠是否更喜欢探索新物体（NO）而不是熟悉的物体（FO）

. Mice that remember the FO are expected to spend more time exploring the NO, resulting in a DI score above 0. Notably, three C58/J strain mice exhibited a clear lack of preference for novelty in both short- and long-term memory trials, with DI scores below 0. However, the mean DI was not significantly different from the control strain, suggesting no alterations in short- or long-term recognition memory in C58/J mice..

。值得注意的是，在短期和长期记忆试验中，三只C58/J品系小鼠明显缺乏对新颖性的偏好，DI评分低于0。然而，平均DI与对照菌株没有显着差异，表明C58/J小鼠的短期或长期识别记忆没有改变。。

It is noteworthy that the C58/J strain exhibits hyperactivity in the open-field test, as demonstrated by our results and previous studies

值得注意的是，正如我们的结果和先前的研究所证明的那样，C58/J菌株在野外试验中表现出过度活跃

. This hyperactivity could significantly influence the performance of C58/J mice during the NOR test, as both tasks utilized a relatively large arena, which contrasts with the smaller, more confined chamber used for contextual fear conditioning (see below). The larger arena allows for higher levels of exploration, which may impact recognition memory assessments.

这种过度活跃可能会在NOR测试期间显着影响C58/J小鼠的表现，因为这两项任务都使用了相对较大的舞台，这与用于情境恐惧条件反射的较小，更封闭的房间形成对比（见下文）。更大的舞台允许更高水平的探索，这可能会影响识别记忆评估。

Therefore, further evaluations are needed to determine whether hyperactivity-related alterations in attentional processes contribute to potential deficits in memory..

因此，需要进一步的评估来确定注意过程中与多动相关的改变是否会导致潜在的记忆缺陷。。

On the other hand, on day 3 of contextual fear memory testing, C58/J mice displayed significantly lower levels of freezing and correspondingly higher levels of movement compared to control mice. This pattern was also observed during the acquisition phase on Day 2, where most control mice spent less time moving, while all C58/J mice moved for close to the full 180-s duration of the test, although this difference was not statistically significant.

另一方面，在情境恐惧记忆测试的第3天，与对照小鼠相比，C58/J小鼠显示出显着更低的冷冻水平和相应更高的运动水平。在第2天的采集阶段也观察到这种模式，其中大多数对照小鼠花费较少的时间移动，而所有C58/J小鼠移动接近整个180秒的测试持续时间，尽管这种差异没有统计学意义。

These findings may be associated with either the inability of C58/J mice to retrieve aversive memory or their tendency toward hyperactive behavior..

这些发现可能与C58/J小鼠无法恢复厌恶记忆或其过度活跃行为的倾向有关。。

Since the dentate gyrus (DG) and CA3 hippocampal regions have been implicated in the performance of this task

由于齿状回（DG）和CA3海马区参与了这项任务的执行

, alterations in C58/J mice may be linked to dysregulation of synaptic transmission and reduced synaptic potentiation at the MF–CA3 synapses. Moreover, we recently reported alterations in the juvenile neurogenic process in the DG of the C58/J strain, particularly a slower maturation trajectory of newborn DG granule cells.

，C58/J小鼠的改变可能与突触传递失调和MF–CA3突触突触增强作用降低有关。此外，我们最近报道了C58/J菌株DG中幼年神经原性过程的改变，特别是新生DG颗粒细胞的成熟轨迹较慢。

. It is known that axons from newborn granule cells contribute to the infrapyramidal Mossy Fiber tract

众所周知，新生颗粒细胞的轴突有助于锥体下苔藓纤维束

. Thus, impaired DG neurogenesis may be contributing to the decreased magnitude of LTP at MF–CA3 synapses, which, in turn, impacts the processing of contextual memory.

因此，受损的DG神经发生可能导致MF–CA3突触的LTP幅度降低，进而影响情境记忆的处理。

However, hyperactivity may be an important factor influencing poor performance in this test, as it could alter the attentional processes needed for C58/J mice to recognize the contextual chamber as an aversive environment or interfere with their ability to exhibit immobility. Interestingly, other murine models of autism, such as the .

然而，多动症可能是影响该测试表现不佳的重要因素，因为它可能会改变C58/J小鼠将情境室识别为厌恶环境或干扰其表现出不动的能力所需的注意过程。有趣的是，其他自闭症小鼠模型，例如。

Brinp1

布林1

-/-

model and the

模型和

Cc2d1a/Cc2d1b

double loss-of-function model, have also been found to display both impaired memory and hyperactivity

双功能丧失模型，也被发现表现出记忆障碍和多动

. Further evaluations focusing on hyperactivity and its impact on attentional processes and memory performance in this strain should be conducted.

。应进行进一步的评估，重点是多动症及其对这种菌株的注意过程和记忆表现的影响。

In conclusion, our findings suggest that polymorphisms in genes encoding key proteins involved in synaptic regulation negatively affect the establishment of passive and active electrophysiological properties and impaired synaptic plasticity of CA3 PCs. Taken together, the changes that occur from the molecular to the cellular level affect the functioning of the hippocampal circuitry and may contribute to the deficits in memory performance commonly associated with idiopathic ASD..

总之，我们的研究结果表明，编码参与突触调节的关键蛋白的基因多态性会对CA3 PC的被动和主动电生理特性的建立以及突触可塑性受损产生负面影响。综上所述，从分子水平到细胞水平发生的变化会影响海马回路的功能，并可能导致通常与特发性ASD相关的记忆表现缺陷。。

Methods

方法

Animals

动物

Male mice aged 10–11 weeks from C57BL/6J and C58/J strains were used for electrophysiological evaluation (5 to 6 animals per strain), FASS-LTP experiments (4 per strain), and behavioral testing (8 per strain). Both strains were procured from The Jackson Laboratory (BHB, ME, USA). The litters, segregated by sex, were individually housed in cages and provided with a commercial pelletized diet (T.G.

来自C57BL/6J和C58/J菌株的10-11周龄雄性小鼠用于电生理评估（每株5至6只动物），FASS-LTP实验（每株4只）和行为测试（每株8只）。两种菌株均购自杰克逊实验室（BHB，ME，USA）。按性别分开的窝仔被单独关在笼子里，并提供商业颗粒饮食（T.G。

rodent diet T2018S.15, Envigo) ad libitum. They were maintained under a reversed 12:12 h light/dark cycle, with lights on from 19:00 to 07:00..

啮齿动物饮食T2018S.15，Envigo）随意。它们保持在12:12小时光照/黑暗的反向循环下，从19:00到07:00开灯。。

In silico

还有二氧化硅。

evaluation of single-nucleotide polymorphisms (SNPs) in synaptic genes

突触基因单核苷酸多态性（SNPs）的评价

We obtained information on genes encoding postsynaptic (5515 genes), presynaptic (2853 genes), and presynaptic vesicle proteins (2476 genes) from the Synaptome.db database

我们从Synaptome.db数据库中获得了编码突触后（5515个基因）、突触前（2853个基因）和突触前囊泡蛋白（2476个基因）的基因信息

Using the Sanger4 Dataset

使用Sanger4数据集

available in the SNP data retrieval utility tool of the Mouse Phenome Database (MPD)

可在小鼠表型数据库（MPD）的SNP数据检索实用工具中获得

, we consulted the C58/J mice genome and searched for coding non-synonymous (Cn) SNPs that resulted in changes to the coding amino acid sequence in the synaptic genes reported by the Synaptome.db database, in comparison to the genome of the C57BL/6J wild-type strain.

，我们咨询了C58/J小鼠基因组，并搜索了编码非同义（Cn）SNP，与C57BL/6J野生型菌株的基因组相比，这些SNP导致Synaptome.db数据库报告的突触基因中编码氨基酸序列的变化。

We also consulted genes encoding proteins associated with the induction of LTP in humans, as reported in the KEGG PATHWAY Database (Pathway: hsa04720)

我们还参考了KEGG途径数据库（途径：hsa04720）中报道的编码与人类LTP诱导相关的蛋白质的基因

, genes differentially expressed during LTP induction in mice, as documented by the study of Bliim and colleagues

，Blim及其同事的研究表明，在小鼠LTP诱导过程中差异表达的基因

, and genes encoding subunits of potassium channels (KCN), as reported by the HUGO Gene Nomenclature Committee at the European Bioinformatics Institute (HGNC)

，以及欧洲生物信息学研究所（HGNC）HUGO基因命名委员会报告的编码钾通道亚基（KCN）的基因

. LTP and KCN-associated genes were analyzed for Cn SNPs in C58/J mice.

分析了C58/J小鼠中LTP和KCN相关基因的Cn SNP。

All genes with Cn SNPs identified in C58/J mice were further analyzed for human orthologs previously associated with ASD, as reported in the SFARI GENE database

根据SFARI基因数据库的报道，对C58/J小鼠中鉴定出的所有具有Cn SNP的基因进行了进一步分析，以寻找先前与ASD相关的人类直系同源基因

We used the STRING platform

我们使用了字符串平台

to obtain a protein interaction network (PPI) of proteins encoded by all the genes with Cn SNPs associated with synapses, LTP induction, and K

为了获得由所有与突触、LTP诱导和K相关的Cn SNPs基因编码的蛋白质相互作用网络（PPI）

channels. A minimum interaction score of 0.700 (high confidence) was required. Additionally, we applied the K-means clustering algorithm to define gene modules based on tightly connected nodes.

渠道。最低交互得分为0.700（高可信度）。此外，我们应用K均值聚类算法来定义基于紧密连接节点的基因模块。

For the synaptic genes associated with ASD and LTP-related genes with Cn SNPs in C58/J mice, we conducted a Gene Ontology (GO) enrichment analysis in the Biological process category and the Human Phenotype Ontology using the g:Profiler platform (version e108_eg55_p17_9f356ae)

对于与C58/J小鼠中具有Cn SNP的ASD和LTP相关基因相关的突触基因，我们使用g：Profiler平台（版本e108\u eg55\u p17\u 9f356ae）在生物过程类别和人类表型本体中进行了基因本体（GO）富集分析

. Each gene module obtained through K-means clustering was also evaluated through GO enrichment analysis in the Molecular function category.

通过K均值聚类获得的每个基因模块也通过分子功能类别中的GO富集分析进行了评估。

FASS-LTP

Procedures for synaptosome isolation, cLTP induction, and flow cytometry corresponding to the FASS-LTP methodology were carried out based on well-established procedures reported by Prieto and colleagues

根据Prieto及其同事报道的成熟程序，进行了与FASS-LTP方法相对应的突触体分离，cLTP诱导和流式细胞术程序

Synaptosome preparation and stimulation

突触体的制备和刺激

Hippocampi were dissected from four 10-week-old male mice of each strain. Tissues were homogenized at 4 °C in a 1.5 mL buffer solution of 320 mM sucrose and 10 mM HEPES (pH 7.4). A protease/phosphatase inhibitor cocktail (5 μg/ml Pepstatin A, Leupeptin, Antipain, Aprotinin, 1 mM PMSF, 1 μM Na

从每种菌株的四只10周龄雄性小鼠中解剖海马。将组织在320 mM蔗糖和10 mM HEPES（pH 7.4）的1.5 mL缓冲溶液中于4°C匀浆。蛋白酶/磷酸酶抑制剂混合物（5g/ml胃抑素A，亮肽素，抗菌素，抑肽酶，1mm PMSF，1m Na

VO公司

) was added. The homogenates were centrifuged at 1200xg for 10 min at 4 °C. The resulting supernatant (S1) was transferred to a clean microfuge tube and then centrifuged at 12,000×

)。将匀浆在4℃下以1200xg离心10分钟。将产生的上清液（S1）转移到干净的微量离心管中，然后以12000离心

克

for 20 min at 4 °C. The new supernatant (S2) was discarded, and the crude synaptosome P2 fraction was resuspended in 1.5 mL of either a basal solution (120 mM NaCl, 3 mM KCl, 2 mM CaCl

在4°C下放置20分钟。丢弃新的上清液（S2），将粗突触体P2级分重悬于1.5 mL基础溶液（120 mM NaCl，3 mM KCl，2 mM CaCl）中

, 2 mM MgCl

，2[UNK]mMMgCl

, 15 mM Glucose, 15 mM HEPES, pH 7.4) or a cLTP solution (125 mM NaCl, 2 mM CaCl

，15 mM葡萄糖，15 mM HEPES，pH 7.4）或cLTP溶液（125 mM NaCl，2 mM CaCl

, 5 mM KCl, 10 mM HEPES, 30 mM Glucose, pH 7.4). Both synaptosome preparations were placed in a 30 mm petri dish, and the volume was adjusted to 2 mL with either basal or cLTP solution. P2 fractions were maintained under gentle agitation for 15 min at room temperature.

，5 mM KCl，10 mM HEPES，30 mM葡萄糖，pH 7.4）。将两种突触体制剂置于30毫米培养皿中，并用基础溶液或cLTP溶液将体积调节至2毫升。P2馏分在室温下轻轻搅拌15分钟。

Cytometry tubes, basal, cLTP, glycine, and KCl solutions were pre-warmed for 5 min in a 37 °C bath, and 180 L (50–200 μg protein) of the synaptosome preparations (cLTP and basal) were transferred. Stimulation was conducted by adding 20 μL of a glycine solution (5 mM glycine, 0.001 mM strychnine, 0.02 mM bicuculline methiodide, final [glycine] = 500 μM) for 15 min in a 37 °C bath to prime synaptic NMDAR.

将细胞计数管，基础，cLTP，甘氨酸和KCl溶液在37°C浴中预热5分钟，然后转移180 L（50–200μg蛋白质）的突触体制剂（cLTP和基础）。通过在37°C浴中加入20μL甘氨酸溶液（5 mM甘氨酸，0.001 mM士的宁，0.02 mM荷包牡丹碱甲碘化物，最终[甘氨酸]=500μM）15分钟来进行刺激，以引发突触NMDAR。

Simultaneously, 20 μL of the basal solution was added to the synaptosome preparation corresponding to the basal condition..

同时，将20μL基础溶液添加到对应于基础条件的突触体制剂中。。

Next, depolarization of synaptosomes was induced by adding 100 μL of a high-concentration KCl solution (50 mM NaCl, 2 mM CaCl

接下来，通过添加100μL高浓度KCl溶液（50 mM NaCl，2 mM CaCl）诱导突触体去极化

, 100 mM KCl, 30 mM Glucose, 0.5 mM Glycine, 0.001 mM strychnine, 0.02 mM bicuculline methiodide, pH 7.4, final [KCl] = 37 mM) to the cLTP synaptosome preparation for 30 min in a 37 °C bath. Simultaneously, 100 μL of the basal solution was added to the synaptosome preparation corresponding to the basal condition..

，100 mM KCl，30 mM葡萄糖，0.5 mM甘氨酸，0.001 mM士的宁，0.02 mM荷包牡丹碱甲碘化物，pH 7.4，最终[KCl]=37 mM）在37°C浴中加入cLTP突触体制剂30分钟。同时，将100μL基础溶液添加到对应于基础条件的突触体制剂中。。

After KCl stimulation, the reaction was stopped by adding 0.5 mL of ice-cold 0.1 mM EDTA-PBS, pH 7.4, to both the cLTP and basal synaptosome preparations.

KCl刺激后，通过向cLTP和基础突触体制剂中加入0.5 mL冰冷的0.1 mM EDTA-PBS（pH 7.4）来终止反应。

Immunolabeling and flow cytometry analysis

免疫标记和流式细胞术分析

4 mL of blocking buffer (PBS-FBS 5%) were added to the cLTP and the basal synaptosome preparation tubes; contents were then centrifuged at 2,500xg for 6 min at 4 °C. The supernatant was decanted, and the pellet was gently resuspended by hand agitation.

将4 mL封闭缓冲液（PBS-FBS 5%）添加到cLTP和基础突触体制备管中；然后将内容物在4°C下以2500xg离心6分钟。倾析上清液，并通过手动搅拌轻轻重悬沉淀。

Both synaptosome preparations were incubated with anti-GluA1 (Cell signaling, #13185, 1:400) and anti-Nrx1β (NeuroMab Facility, #CAT, 1:400) antibodies for 30 min at 4 °C, under agitation. After incubation, synaptosome preparations were washed with 4 mL of blocking buffer and centrifuged at 2500×

将两种突触体制剂与抗GluA1（Cell signaling，#13185，1:400）和抗Nrx1β（NeuroMab Facility，#CAT，1:400）抗体在4°C搅拌下孵育30分钟。孵育后，用4 mL封闭缓冲液洗涤突触体制剂，并在2500℃下离心

克

for 6 min at 4 °C. The supernatant was decanted, and the pellet was gently resuspended in the remaining solution. Subsequently, 2.5 μg/mL of anti-rabbit Alexa Fluor 488 (Invitrogen, #A-11034) and anti-mouse Alexa Fluor 647 (Invitrogen, #A-21236) secondary antibodies in 400 μL of blocking buffer solution were added to both synaptosome preparations.

。倾析上清液，将沉淀轻轻重悬于剩余溶液中。随后，将400μL封闭缓冲液中的2.5μg/mL抗兔Alexa Fluor 488（Invitrogen，#A-11034）和抗小鼠Alexa Fluor 647（Invitrogen，#A-21236）二抗添加到两种突触体制剂中。

Secondary antibodies were incubated for 30 min at 4 °C in the dark. After incubation, synaptosome preparations were washed with 4 mL of blocking buffer and centrifuged at 2500×.

将二抗在黑暗中于4°C孵育30分钟。孵育后，用4 mL封闭缓冲液洗涤突触体制剂，并以2500倍离心。

克

for 6 min at 4 °C. The supernatant was decanted, and the pellet was gently resuspended in 400 μL of blocking buffer solution and acquired immediately on a FacsCanto II flow cytometer (B.D. Biosciences, equipped with 488-nm blue laser and 633-nm red laser) using FACS Diva software. A synaptosome preparation in basal solution incubated only with secondary antibodies was used for background fluorescence control (Supplementary Fig.

。倾析上清液，将沉淀轻轻重悬于400μL封闭缓冲溶液中，并使用FACS Diva软件立即在FacsCanto II流式细胞仪（B.D.Biosciences，配备488 nm蓝色激光和633 nm红色激光）上采集。仅与二抗孵育的基础溶液中的突触体制剂用于背景荧光控制（Supplementary Fig.）。

S2级

C).

C）。

Size gates were defined in FSC-SSC plots using calibrated beads (1–3 μm). Then, ten thousand single-particles were acquired based on FSC-A and FSC-H plots (Supplementary Fig.

使用校准的珠子（1-3μm）在FSC-SSC图中定义大小门。然后，基于FSC-A和FSC-H图获得了10000个单个颗粒（Supplementary Fig.）。

S2级

A,B). The signal corresponding to GluA1

A、 B）。对应于GluA1的信号

/Nrx1β

Nrx1b

synaptosomes was detected by Alexa Fluor-488 (B.P. filter 530/30) and Alexa Fluor-647 (B.P. filter 660/20) fluorescence. Signals were collected using log amplification and analyzed with FlowJo 10.8.1 software.

通过Alexa Fluor-488（B.P.过滤器530/30）和Alexa Fluor-647（B.P.过滤器660/20）荧光检测突触体。使用对数放大收集信号，并使用FlowJo 10.8.1软件进行分析。

Acute slice preparation

急性切片制备

Deep anesthesia was induced with sodium pentobarbital (50 mg/kg) before decapitation; the brain was placed into an ice-cold sucrose solution containing (in mM) 210 sucrose, 2.8 KCl, 2 MgSO

断头前用戊巴比妥钠（50 mg/kg）诱导深度麻醉；将大脑置于含有210蔗糖，2.8 KCl，2 MgSO的冰冷蔗糖溶液中

, 1.25 Na

，1.25纳

HPO

, 25 NaHCO

，25碳酸氢钠

, 1 MgCl

，1氯化镁

, 1 CaCl

，1氯化钙

, and 10 D-glucose. The solution was continuously bubbled with a carbogen mixture (95% O

，和10 D-葡萄糖。该溶液连续鼓泡含碳混合物（95%O

/5% CO

/5%一氧化碳

). Tissue blocks containing the hippocampus and surrounding structures were sliced at 385 µm thickness in the transversal plane using a vibrating tissue slicer (Leica VT1000S; Nussloch, Germany). The acute slices were stabilized at 34 °C for 30 min in an artificial cerebrospinal fluid (aCSF) solution containing (in mM) 125 NaCl, 2.5 KCl, 1.25 Na.

)。使用振动组织切片机（Leica VT1000S；Nussloch，Germany）在横向平面上将含有海马和周围结构的组织块切成385µm厚。将急性切片在含有（以mM计）125 NaCl，2.5 KCl，1.25 Na的人工脑脊液（aCSF）溶液中于34°C稳定30分钟。

HPO

, 25 NaHCO

，25碳酸氢钠

, 4 MgCl

，4氯化镁

, 1 CaCl

，1氯化钙

, and 10 D-glucose. Then, the slices were maintained at room temperature for at least 90 min before any experimental procedure. A slice was transferred to a submerged chamber (total volume: 400 µL) and perfused with aCSF containing (in mM): 125 NaCl, 2.5 KCl, 1.25 Na

，和10 D-葡萄糖。然后，在任何实验程序之前，将切片在室温下保持至少90分钟。将切片转移到浸没室（总体积：400µL）中，并用含有（以mM为单位）125 NaCl，2.5 KCl，1.25 Na的aCSF灌注

HPO

, 25 NaHCO

，25碳酸氢钠

, 2 MgCl

，2氯化镁

, 2 CaCl

，2氯化钙

, and 10 D-glucose, and pH ≈ 7.30–7.35. All electrophysiological recordings were performed at 33 ± 1 °C.

，和10 D-葡萄糖，pH≈7.30-7.35。所有电生理记录均在33±1°C下进行。

Whole-cell patch-clamp recordings

全细胞膜片钳记录

Whole-cell patch-clamp recordings were performed in dorsal hippocampal slices. Once transferred to the recording chamber, the slice was visualized with infrared DIC optics coupled to an FN1 Eclipse microscope (Nikon Corporation, Minato, Tokyo, Japan), and CA3b pyramidal cells were identified based on shape and position within the stratum pyramidale.

在背侧海马切片中进行全细胞膜片钳记录。一旦转移到记录室，切片用与FN1 Eclipse显微镜（Nikon Corporation，Minato，Tokyo，Japan）耦合的红外DIC光学器件可视化，并根据锥体层内的形状和位置识别CA3b锥体细胞。

The patch pipettes were pulled from borosilicate glass using a micropipette puller (P97, Sutter Instruments, Novato, CA, USA). The pipette tips had a resistance of 4–6 MΩ when filled with an intracellular solution with the following composition (in mM): 135 K.

使用微量移液器拔出器（P97，Sutter Instruments，Novato，CA，USA）从硼硅酸盐玻璃中拔出贴片移液器。当填充具有以下成分（以毫米为单位）的细胞内溶液时，移液器吸头的电阻为4-6 MΩ：135 K。

-gluconate, 10 KCl, 5 NaCl, 1 EGTA, 10 HEPES, 2 Mg

-葡萄糖酸盐，10 KCl，5 NaCl，1 EGTA，10 HEPES，2 Mg

-ATP, 0.4 Na

-ATP，0.4 Na

-GTP, 10 phosphocreatine, and pH ≈ 7.20–7.28. The patch-clamp recordings were performed with an Axopatch 200B amplifier (Molecular Devices, San José, CA, USA), digitized at a sampling rate of 10 kHz, and filtered at 5 kHz with a Digi Data 1322A (Axon Instruments, Palo Alto, CA, USA). Digital signals were acquired and analyzed offline with the help of pCLAMP 11.2 software (Molecular Devices, San Jose, CA)..

-GTP，10磷酸肌酸和pH≈7.20-7.28。膜片钳记录使用Axopatch 200B放大器（Molecular Devices，San José，CA，USA）进行，以10 kHz的采样率数字化，并使用Digi Data 1322A（Axon Instruments，Palo Alto，CA，USA）以5 kHz进行滤波。借助pCLAMP 11.2软件（Molecular Devices，San Jose，CA）离线采集和分析数字信号。。

Determination of passive and active electrophysiological properties

被动和主动电生理特性的测定

Determination of the resting membrane potential (RMP) was performed after the initial pipette break-in from giga-seal to the whole-cell configuration. Therefore, the amplifier configuration was switched to current-clamp mode, and the measurement was performed. Next, a series of current injections (1 s duration, 30 pA increments) was applied to determine the current–voltage relationship (I–V relationship), somatic input resistance (R.

静息膜电位（RMP）的测定是在初始移液管从giga seal进入全细胞构型后进行的。因此，放大器配置被切换到电流钳位模式，并进行了测量。接下来，应用一系列电流注入（持续1秒，增量30 pA）来确定电流-电压关系（I-V关系），体细胞输入电阻（R）。

), membrane time constant (τ

)，膜时间常数（τ

memb

), and rheobase current (

)和流变基电流(

我

Rheo

) required to elicit an action potential (AP). Somatic R

)需要引发动作电位（AP）。体细胞R

was calculated as the slope value of the first-degree polynomial function: (

计算为一次多项式函数的斜率值：(

$f\left(x\right)=mx+b)$

\\（f\left（x\right）=mx+b）

fitted to the I–V relationship around the RMP. t

符合RMP.t周围的I–V关系

memb

was calculated by fitting a single exponential function

通过拟合单个指数函数来计算

$(f\left(t\right)={\sum }_{i=1}^{n}Ai{e}^{-\frac{t}{\tau i}}+C)$

\（（f \左（t \右）={\和}{i=1}^{n}Ai{e} ^{-\frac{t}{\tau i}}+C）\）

to a voltage response elicited by injecting the minimal hyperpolarizing current (–30 pA) that favors passive membrane charge/discharge. A current ramp was injected into the cell to determine the

注入有利于被动膜充电/放电的最小超极化电流（–30 pA）引起的电压响应。向电池中注入电流斜坡以确定

我

Rheo

necessary to elicit one AP. This parameter was used to determine the basal excitability of CA3 pyramidal cells. The firing properties of CA3 pyramidal cells were determined by plotting the relationship between the injected current vs. the recorded output frequency (f

引发一个AP所必需的。该参数用于确定CA3锥体细胞的基础兴奋性。通过绘制注入电流与记录输出频率（f

(I)

（一）

). For these analyses, f

)。对于这些分析，f

(I)

（一）

was plotted against the intensity of the input signal and adjusted to a three-parameter sigmoid function

根据输入信号的强度作图，并调整为三参数S形函数

${f}_{(I)}=a/(1 + {e}^{-k(I-I0 )})$

\\({f}_{（I）}=a/（1+{e}^{-k（I-10）}）

, where

，其中

${f}_{(I)}$

\（笑声）({f}_{（I）}\）

stands for the firing frequency as a function of the injected current (I), and

表示作为注入电流（I）函数的点火频率，以及

is its slope.

是它的坡度。

Action potential (AP) dynamic analysis

动作电位（AP）动态分析

The AP kinetic properties were determined by constructing phase plots; for these, the differential equation

通过构建相图确定AP动力学性质；对于这些，微分方程

$dV/dt$

\（dV/dt）

(mV ms

（毫伏毫秒

−1

) was plotted against the instantaneous membrane potential as previously reported

)

. The resulting loop graph was employed to calculate the AP threshold, amplitude, half-width (H-W), and maximal rates of depolarization and repolarization.

所得的回路图用于计算AP阈值，幅度，半宽（H-W）以及最大去极化和复极速率。

Extracellular recordings

细胞外记录

Extracellular field excitatory postsynaptic potentials (fEPSPs) were used to determine synaptic strength and synaptic plasticity at the Mossy Fiber–CA3 pyramidal cell synapse. The MF fEPSPs were recorded with pipettes pulled from borosilicate glass with resistances of 1–2 MΩ when filled with a NaCl solution (3 M).

细胞外场兴奋性突触后电位（fEPSP）用于确定苔藓纤维-CA3锥体细胞突触的突触强度和突触可塑性。当填充NaCl溶液（3 M）时，用从硼硅酸盐玻璃中拔出的移液管记录MF-fEPSP，电阻为1-2MΩ。

Orthodromic MF fEPSPs were elicited with a bipolar nichrome electrode placed in the hilus, and the recording pipette was placed in the stratum lucidum. The test stimuli (0.067 Hz, 100 µs duration) evoked 30–50% of the maximal MF fEPSP amplitude, previously determined by an input–output curve (current pulses from 0 to 400 µA with 50 µA steps).

用放置在门中的双极镍铬电极引发顺向MF-fEPSP，并将记录移液管放置在灵芝层中。测试刺激（0.067 Hz，持续时间100µs）诱发了最大MF-fEPSP振幅的30–50%，先前由输入-输出曲线确定（电流脉冲从0到400µA，步长为50µA）。

The current pulses were delivered via a high-voltage isolation unit (A365D; World Precision Instruments, Sarasota, FL, USA), controlled with a Master-8 pulse generator (AMPI, Jerusalem, Israel). The responses were amplified with a Dagan BVC-700A amplifier (Minneapolis, MN, USA) coupled to an extracellular headstage (Dagan, model 8024) and high-pass filtered at 0.3 Hz.

电流脉冲通过高压隔离单元（A365D；World Precision Instruments，Sarasota，FL，USA）传递，该单元由Master-8脉冲发生器（AMPI，耶路撒冷，以色列）控制。用与细胞外前端（Dagan，型号8024）耦合的Dagan BVC-700A放大器（美国明尼苏达州明尼阿波利斯）放大响应，并以0.3 Hz进行高通滤波。

Electrical noise suppression was achieved with a Humbug noise eliminator (Quest Scientific Instruments; North Vancouver, BC, Canada). The resulting MF fEPSPs were digitized via the A/D converter BNC-2110 (National Instruments, Austin, Texas), displayed on a PC-based oscilloscope for storage and offline analysis with custom-written software (Lab View 7.1 system, National Instruments, Austin, TX, USA)..

电噪声抑制是通过骗子噪声消除器（Quest Scientific Instruments；加拿大不列颠哥伦比亚省北温哥华）实现的。产生的MF-fEPSP通过A/D转换器BNC-2110（National Instruments，Austin，Texas）数字化，显示在基于PC的示波器上，用于存储和使用自定义编写的软件进行离线分析（Lab View 7.1 system，National Instruments，Austin，TX，USA）。。

The criteria used to identify and accept the evoked responses as MF fEPSPs

用于识别和接受诱发反应的标准为MF-fEPSP

were: 1) the excitatory potential onset latency was < 5 ms; 2) the negative-evoked sink was restricted to the stratum lucidum, and the duration was > 4 ms; 3) the paired-pulse evoked response exhibited strong facilitation; and 4) the evoked responses were depressed by the group II metabotropic glutamate receptor agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV, 5 µM)..

是：1）兴奋性潜在发作潜伏期为5 ms；2）负诱发汇仅限于灵芝层，持续时间>4 ms；3）成对的脉冲诱发反应表现出强烈的促进作用；4）II组代谢型谷氨酸受体激动剂（2S，2'R，3'R）-2-（2'，3'-二羧基环丙基）甘氨酸（DCG-IV，5µM）抑制诱发反应。。

Induction of MF LTP was achieved with high-frequency stimulation (HFS) delivered to the mossy fiber bundle, which consisted of 100 pulses at 100 Hz and was repeated three times at 10-s intervals. The MF fEPSP onset latencies were measured from the end of the electrical artifact to the beginning of the sink of the synaptic response.

MF LTP的诱导是通过向长满苔藓的纤维束传递高频刺激（HFS）来实现的，该纤维束由100 Hz的100个脉冲组成，并以10 s的间隔重复三次。。

MF-evoked PPF with an inter-stimulus interval (ISI) from 40 to 200 ms was determined in a subset of experiments. The MF paired-pulse ratio (PPR) values were expressed as the amplitude ratio between the pair’s second and first MF fEPSP (MF PPR = S2/S1). The change in the MF fEPSP slope was expressed as a percentage of the average MF fEPSP slope recorded during the baseline period..

在一部分实验中确定了刺激间隔（ISI）为40至200 ms的MF诱发的PPF。MF配对脉冲比（PPR）值表示为该对的第二和第一MF fEPSP之间的幅度比（MF PPR=S2/S1）。MF-fEPSP斜率的变化表示为基线期间记录的平均MF-fEPSP斜率的百分比。。

Drugs and chemicals

药物和化学品

Drugs and chemicals used in this study were purchased from Sigma Aldrich (St. Louis, MO, USA), except for DCG-IV, which was purchased from Tocris Biosciences (Bristol, UK).

本研究中使用的药物和化学品购自Sigma-Aldrich（美国密苏里州圣路易斯），但DCG-IV购自Tocris Biosciences（英国布里斯托尔）。

Behavior evaluation

行为评估

All behavioral testing was conducted in an isolated room illuminated by red light at a constant room temperature of 25 °C. All tests were performed between 10:00 am and 2:00 pm (active period of the animals as they were kept under inverted cycle). Before behavioral testing, animals were handled for 3 consecutive days to habituate them to the experimenters and the room conditions.

所有行为测试均在25°C恒定室温下由红光照亮的隔离房间中进行。所有测试均在上午10:00至下午2:00之间进行（动物处于倒置周期的活动期）。在行为测试之前，连续3天处理动物以使其适应实验者和房间条件。

The behavioral tests were carried out in the following order:.

行为测试按以下顺序进行：。

Open field test.

。

The open-field test was used to assess locomotion activity

野外测试用于评估运动活动

in both strains. We used a white polyvinyl chloride (PVC) square-shaped arena (40 cm × 40 cm and 25 cm in height), whose floor was divided with a permanent marker into 16 squares (4 × 4) for later analysis. The arena also featured an internal visual clue consisting of a rectangular black and white striped plasticized cardboard (38 cm × 5 cm), which was glued to one of the walls and maintained on the same wall throughout the experiment..

在两种菌株中。我们使用白色聚氯乙烯（PVC）方形竞技场（40厘米×40厘米，高25厘米），其地板用永久标记分成16个正方形（4×4）用于以后的分析。竞技场还设有一个内部视觉线索，由一块矩形黑白条纹塑化纸板（38厘米×5厘米）组成，该纸板粘在其中一堵墙上，并在整个实验过程中保持在同一面墙上。。

Each mouse was introduced randomly into the arena from one of the corners and allowed to explore freely for 5 min. Following each test, the arena was cleaned using a solution of 50% ethanol and 50% EXTRAN. To analyze locomotion, we quantified the total number of times the animal crossed a square edge across the arena, and the number of times the animal crossed a square edge in the arena’s peripheral and central zones..

将每只小鼠从一个角落随机引入竞技场，并允许其自由探索5分钟。每次测试后，使用50%乙醇和50%EXTRAN的溶液清洁竞技场。为了分析运动，我们量化了动物穿过竞技场方形边缘的总次数，以及动物穿过竞技场外围和中心区域方形边缘的次数。。

Novel object recognition test (NOR).

。

We conducted the Novel Object Recognition test (NOR)

我们进行了新的物体识别测试（NOR）

in both strains to evaluate recognition memory involving the hippocampus. The test consisted of three phases: acquisition, short-term memory trial, and long-term memory trial. The assessment arena was the same as that used in the open-field test. Mice were randomly introduced to the arena from one of the corners opposite the wall where the objects were placed.

在这两种菌株中评估涉及海马的识别记忆。。评估场地与野外测试中使用的场地相同。将小鼠从放置物体的墙壁对面的一个角落随机引入竞技场。

The objects used for the NOR test included Lego blocks (in red, blue, white, and yellow) and glass bottles in various shapes and colors (green and pink, oval, and square-shaped, filled with cement to prevent displacement and falling). The configuration for pairing the objects was randomized to avoid bias towards any object.

用于NOR测试的物体包括乐高积木（红色，蓝色，白色和黄色）和各种形状和颜色的玻璃瓶（绿色和粉红色，椭圆形和方形，填充水泥以防止移位和掉落）。配对对象的配置是随机的，以避免偏向任何对象。

Both objects were placed 10 cm away from each of the two adjacent walls, and the distance between them remained constant. Animals were allowed to explore them freely for 10 min in each trial. The arena and objects were cleaned between evaluations..

两个物体都放置在距离两个相邻墙壁各10厘米的地方，它们之间的距离保持不变。在每次试验中，允许动物自由探索10分钟。竞技场和物体在评估之间被清理。。

In the acquisition phase, two identical objects (A1 + A2) were placed in the arena, and each mouse was allowed to explore them freely. Two hours after the acquisition phase, short-term memory was evaluated by replacing one of the two familiar objects with a novel object (A1 + B). After the exploration, the novel object (B) used in the short-term memory trial became familiar.

在采集阶段，将两个相同的物体（A1+ A2）放置在竞技场中，并允许每只小鼠自由探索它们。在采集阶段两小时后，通过用新物体（A1 + B）替换两个熟悉物体中的一个来评估短期记忆。经过探索，短期记忆试验中使用的新物体（B）变得很熟悉。

Subsequently, the long-term memory evaluation was performed 24 h after the acquisition phase by replacing one of the two familiar objects (A1) with a novel object (B + C)..

随后，在采集阶段后24小时进行长期记忆评估，将两个熟悉的物体（A1）中的一个替换为一个新物体（B+）C）。。

In this test, mice with the ability to remember a familiar object (FO) are expected to spend more time exploring a novel object (NO)

在这项测试中，具有记忆熟悉物体（FO）能力的小鼠预计会花费更多时间探索新物体（否）

To determine whether the two identical objects were explored equally during the acquisition phase, we calculated the exploration index (EI) for each object as follows:

为了确定在采集阶段是否对两个相同的物体进行了均等的探索，我们计算了每个物体的探索指数（EI），如下所示：

$${\text{EI}}\;{\text{for}}\;{\text{Object}}\,1 = \left[ {{\text{Exploration}}\;{\text{time}}\;{\text{ for}}\;{\text{Object}}\;1/{\text{Total}}\;{\text{exploration}}\;{\text{time}}\;\left( {{\text{Object}}\;1 + {\text{Object}}\;2} \right)} \right] * 100$$

$${\文本{EI}}\；{\文本{for}}\；{\ text{Object}}，1=\ left[{\ text{Exploration}}；{\ text{time}}；{\ text{for}}；{\ text{Object}}；1/{\ text{Total}}；{\ text{Exploration}；{\ text{time}}；\ left（{\ text{Object}}；1+{\ text{Object}；2}【右】}【右】*100$$

$${\text{EI}}\;{\text{for}}\;{\text{Object}}\,2 = \left[ {{\text{Exploration}}\;{\text{time}}\;{\text{ for}}\;{\text{Object}}\;2/{\text{Total}}\;{\text{exploration}}\;{\text{time}}\;\left( {{\text{Object}}\;1 + {\text{Object}}\;2} \right)} \right] * 100$$

$${\文本{EI}}\；{\文本{for}}\；{\ text{Object}}，2=\ left[{\ text{Exploration}}；{\ text{time}}；{\ text{for}}；{\ text{Object}}；2/{\ text{Total}}；{\ text{Exploration}；{\ text{time}}；\ left（{\ text{Object}}；1+{\ text{Object}；2}【右】}【右】*100$$

To determine the preference for novelty (NO over FO), we calculated the discrimination index (DI) for the NO as follows:

为了确定对新颖性的偏好（NO优于FO），我们计算了NO的歧视指数（DI），如下所示：

$${\text{DI}}\;{\text{for}}\;{\text{NO}} = \left[ {{\text{Exploration}}\;{\text{time}}\;{\text{for}}\;{\text{N}} - {\text{Exploration}}\;{\text{time}}\;{\text{for}}\;{\text{FO}}/{\text{Total}}\;{\text{exploration}}\;{\text{time}}\;\left( {{\text{FO}} + {\text{NO}}} \right)} \right] \times 100$$

$${\文本{DI}}\；{\文本{for}}\；$$

A DI score above 0 indicates a preference for NO.

DI得分高于0表示偏爱NO。

A DI score of 0 indicates no preference for either object.

DI得分为0表示对任何一个对象都没有偏好。

A DI score below 0 indicates a preference for FO.

DI得分低于0表示偏爱FO。

Contextual fear conditioning task

情境恐惧条件任务

Contextual memory in mice was evaluated using the contextual fear conditioning task, in which the animal learns to predict the presence of an aversive unconditioned stimulus (foot shock) through its association with a specific context, representing the conditioned stimulus. The association between the unconditioned and conditioned stimuli induces a classical fear response in rodents known as immobility or freezing.

使用情境恐惧条件化任务评估小鼠的情境记忆，其中动物通过与特定情境的关联来学习预测厌恶性无条件刺激（足部休克）的存在，代表条件刺激。无条件刺激和条件刺激之间的关联在啮齿动物中引起了经典的恐惧反应，称为不动或冻结。

Animals were placed in a conditioning chamber (26.7 cm × 26.7 cm and 26 cm in height) featuring electrified metal rods on the base (San Diego Instruments) and a grid of infrared beams interrupted by the animal’s movement. The test comprised two phases: acquisition and memory. The acquisition trial was conducted once per day for two consecutive days.

将动物放置在调理室（26.7厘米×26.7厘米和26厘米高）中，底座上有带电的金属棒（圣地亚哥仪器公司）和被动物运动中断的红外光束网格。测试包括两个阶段：获取和记忆。收购试验连续两天每天进行一次。

On both days, each mouse was introduced into the chamber to be let to explore freely for 180 s, after which it received an electrical shock through the floor rods (intensity of 0.7 A) for 2 s; the animals stayed in the cage for another 20 s after the shock and were then retrieved and placed back in their home cage.

在这两天，将每只小鼠引入室内，让其自由探索180 s，然后通过地板杆（强度为0.7 A）电击2 s；休克后，这些动物在笼子里再呆20秒，然后被取回并放回家中的笼子。

Freezing behavior was analyzed only during pre-shock time. On the third day, the memory evaluation trial was carried out by placing each mouse in the chamber for free exploration for 180 s without administering a shock..

仅在冲击前时间分析冻结行为。在第三天，通过将每只小鼠置于室内进行180秒的自由探索而不进行电击来进行记忆评估试验。。

Movement and freezing behavior from each animal were visually assessed by the experimenter, recorded for further analysis, and automatically recorded (in 5-s blocks) using the Freeze Monitor System software (The San Diego Instruments Freeze Monitor System).

实验者对每只动物的运动和冷冻行为进行视觉评估，记录以供进一步分析，并使用Freeze Monitor系统软件（圣地亚哥仪器冷冻监控系统）自动记录（以5秒为单位）。

Statistical analysis

统计分析

The results corresponding to the electrophysiological evaluation are expressed as mean ± SEM. The results corresponding to the FASS-LTP assay and the behavioral evaluation are expressed as mean ± SD. The violin plots show the median, interquartile range, and individual data. The statistical comparisons were performed between the C57BL/6J control strain and the C58/J model of autism.

对应于电生理评估的结果表示为平均值±SEM。对应于FASS-LTP测定和行为评估的结果表示为平均值±SD。小提琴图显示中位数，四分位间距和个体数据。。

Animals’ evaluation was blinded to the experimenters to avoid any possible source of bias. The normality distribution of all data was validated with the Kolmogorov–Smirnov test (p = 0.05). The comparability between experimental conditions was evaluated by two-tailed unpaired Student’s .

动物的评估对实验者不知情，以避免任何可能的偏见来源。所有数据的正态分布均通过Kolmogorov–Smirnov检验进行了验证（p=0.05）。实验条件之间的可比性由两尾不成对学生评估。

-test, Welch’s t-test, Mann–Whitney test, two-way repeated measures (RM) ANOVA, or two-way ANOVA, as appropriate. When F achieved minimal statistical significance, the Sidak or Tukey post hoc tests were used for multiple comparisons. Statistical significance was set at p < 0.05. Statistical analyses were performed using GraphPad Prism 10.2.1.

-测试，韦尔奇t检验，曼-惠特尼检验，双向重复测量（RM）方差分析或双向方差分析（视情况而定）。当F达到最小的统计学显着性时，使用Sidak或Tukey事后检验进行多重比较。。

All fits were performed using Clampfit 10.7 (Molecular Devices). All data obtained from the previous statistical analyses are described in detail in Supplementary Table .

使用Clampfit 10.7（Molecular Devices）进行所有拟合。补充表中详细描述了从以前的统计分析中获得的所有数据。

S2级

For the in silico evaluation, to perform the GO enrichment analysis, we used g:Profiler (version e108_eg55_p17_9f356ae), which considers a result statistically significant if it corresponds to an experiment-wide threshold of α = 0.05 after applying the g:SCS multiple testing correction method. The enriched GO terms were plotted using the log10 of p-adjusted values.

对于计算机评估，为了进行GO富集分析，我们使用了g:Profiler（版本e108\U eg55\U p17\U 9f356ae），如果在应用g后对应于实验范围的阈值α=0.05，则认为结果具有统计学意义：SCS多重测试校正方法。使用p调整值的log10绘制富集的GO项。

The .

的。

Gene Ratio

基因比率

was calculated by dividing the number of requested genes found in the functional category by the number of genes in the experimental gene set. The

通过将功能类别中发现的请求基因数量除以实验基因组中的基因数量来计算。The

Rich Factor

丰富的因素

was calculated by dividing the number of requested genes found in the functional category by the total number of genes within that specific functional category.

通过将功能类别中发现的请求基因数量除以该特定功能类别中的基因总数来计算。

Data availability

数据可用性

All data generated or analyzed during this study are included in this published article (and its Supplementary Information files). All SNP IDs and the genome reference of the C57BL/6J strain consulted for the analysis performed in the SNP data retrieval utility tool of the Mouse Phenome Database (Sanger4 dataset), are available in the European Nucleotide Archive [Assembly Name: GRCm38.p4.

本研究期间生成或分析的所有数据均包含在本文（及其补充信息文件）中。在小鼠表型数据库（Sanger4数据集）的SNP数据检索实用工具中进行的分析所参考的所有SNP ID和C57BL/6J菌株的基因组参考均可在欧洲核苷酸档案库中获得[程序集名称：GRCm38.p4]。

Accession: GCA_000001635]..

加入：GCA\u000001635]。。

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Acknowledgements

致谢

We thank Patricia Ferrera for her technical assistance in lab management. R. Olvera for exploratory patch-clamp experiments, and Mónica Martínez-Marcial, Daniel Garzón-Cortés, and Jorge Omar Rebollar-García for assistance with animal breeding, care, and management.

我们感谢Patricia Ferrera在实验室管理方面提供的技术援助。R、 Olvera进行探索性膜片钳实验，Mónica Martínez Marcial，Daniel Garzón-Cortés和Jorge Omar Rebollar García协助动物繁殖，护理和管理。

Funding

资金

This work was supported Programa de Apoyo a Proyectos de Investigacion e Innovacion Tecnologica (PAPIIT) IN207123 and IN217323, and CONAHCyT [No. 319636], Ciencia de Frontera.

这项工作得到了207123年和217323年研究和技术创新项目支助方案以及前沿科学国家科学研究中心[319636号]的支持。

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Author notes

作者笔记

Isabel Barón-Mendoza and Luis A. Márquez contributed equally to this article.

伊莎贝尔·巴龙·门多萨（IsabelBarón-Mendoza）和路易斯·马尔克斯（LuisA.Márquez）对本文的贡献相同。

Authors and Affiliations

作者和隶属关系

Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico

墨西哥国立自治大学生物医学研究所基因组医学和环境毒理学系，04510，墨西哥城，墨西哥

Isabel Barón-Mendoza, Aliesha González Arenas, Jessica Guzmán-Condado, Montserrat Mejía-Hernández & Angélica Zepeda

伊莎贝尔·巴隆-门多萨、阿利莎·冈萨雷斯·阿里纳斯、杰西卡·古兹曼-县、蒙特塞拉特·梅亚-埃尔南德斯和安吉丽卡·泽佩达

Departamento de Farmacobiología, CINVESTAV Unidad Sur CdMx, Mexico City, Mexico

墨西哥城CDMX南部Cinvestav单位药物生物学系

Luis A. Márquez, Vladimir A. Martínez-Rojas, Johaly Anguiano-Buenfil & Emilio J. Galván

路易斯A。马尔克斯，弗拉基米尔A。马丁内斯-罗哈斯，约翰利·安吉亚诺-布恩菲尔和埃米利奥J。加尔文

Laboratorio de Neuroinmunobiología, Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología UNAM, Cuernavaca, Morelos, 62210, Mexico City, Mexico

墨西哥莫雷洛斯库埃纳瓦卡联合国大学生物技术研究所分子医学和生物过程系神经免疫生物学实验室，墨西哥城62210

Jorge Luis Almazán, Leonor Pérez-Martínez & Gustavo Pedraza-Alva

豪尔赫·路易斯·阿尔马赞、莱昂诺尔·佩雷斯-马丁内斯和古斯塔沃·佩德拉扎-阿尔瓦

Centro de Investigaciones Sobre El Envejecimiento, CIE-Cinvestav, México City, Mexico

老龄化研究中心，CIE-Cinvestav，墨西哥城，墨西哥

Emilio J. Galván

埃米利奥·加尔万

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Isabel Barón-Mendoza

伊莎贝尔·巴隆-门多萨

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Luis A. Márquez

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Jessica Guzmán-Condado

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Vladimir A. Martínez-Rojas

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Montserrat Mejía-Hernández

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Jorge Luis Almazán

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Gustavo Pedraza-Alva

古斯塔沃·佩德拉扎·阿尔瓦

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Emilio J. Galván

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Angélica Zepeda

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Contributions

捐款

I.B.M., A.G.A. E.J.G. L.P.M., G.P.A. and A.Z. designed study; I.B.M. and M.M.H. performed in-silico analysis, L.A.M and J.A.B. performed electrophysiological experiments; J.G.C. performed behavioral experiments; J.L.A. performed cLTP experiments; I.B.M., M.H.M and A.G.A collected and/or assembled and analysed in silico data; ; J.L.A, I.B.M., A.G.A, L.P.M.

一、 B.M.，A.G.A.E.J.G.L.P.M.，G.P.A.和A.Z.设计的研究；一、 B.M.和M.M.H.进行了计算机分析，L.A.M和J.A.B.进行了电生理实验；J、 G.C.进行了行为实验；J、洛杉矶进行了cLTP实验；一、 B.M.，M.H.M和A.G.A收集和/或组装并分析了计算机数据；J、洛杉矶，I.B.M.，A.G.A，L.P.M。

and G.P.A. collected and/or assembled and analysed cLTP data; L.A.M., J.A.B., V.A.M.R., E.J.G. collected and/or assembled and analysed electrophysiology data; J.G.C., I.B.M. and A.Z. assembled and analysed behavioral data; I.B.M., L.A.M., A.G.A., E.J.G. and A.Z. wrote manuscript..

和G.P.A.收集和/或组装并分析cLTP数据；五十、 A.M.，J.A.B.，V.A.M.R.，E.J.G.收集和/或组装并分析电生理数据；J、 G.C.，I.B.M.和A.Z.收集并分析了行为数据；一、 B.M.，L.A.M.，A.G.A.，E.J.G.和A.Z.撰写了手稿。。

Corresponding authors

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Correspondence to

通信对象

Emilio J. Galván

埃米利奥·加尔万

或

Angélica Zepeda

当归

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Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

Ethical approval

道德认可

All animal procedures were carried out following the ARRIVE Guidelines

所有动物程序均按照ARRIVE指南进行

and were performed in agreement with local government rules (Official Mexican Standard NOM-062-ZOO-1999) and the local Institutional Animal Care and Research Advisory Committees (CICUAL, ID 10367) from the Universidad Nacional Autónoma de México (UNAM) and the protocols authorized by the internal ethics committee of CINVESTAV (CICUAL, Protocol number 0090-14), which mandate the minimization of suffering and the number of experimental animals used..

。。

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Supplementary Information

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Supplementary Figures.

补充数字。

Supplementary Table S1.

补充表S1。

Supplementary Table S2.

补充表S2。

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Barón-Mendoza, I., Márquez, L.A., Arenas, A.G.

男爵-门多萨，I.，马尔克斯，L.A.，阿里纳斯，A.G。

et al.

等人。

Single-nucleotide polymorphism analysis accurately predicts multiple impairments in hippocampal activity and memory performance in a murine model of idiopathic autism.

单核苷酸多态性分析可准确预测特发性自闭症小鼠模型中海马活动和记忆表现的多种损伤。

Sci Rep

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, 749 (2025). https://doi.org/10.1038/s41598-024-84521-x

749 (2025).https://doi.org/10.1038/s41598-024-84521-x

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2024年6月7日

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