A new study suggests a potential molecular strategy for treating fragile X syndrome, an inherited neurodevelopmental disorder that causes autism spectrum disorder and intellectual disability. This work shows that enhancing the function of the GluN2b subunit of the

一项新的研究表明，治疗脆性X综合征（一种导致自闭症谱系障碍和智力障碍的遗传性神经发育障碍）可能存在一种潜在的分子策略。这项工作表明，增强GluN2b亚基的功能可以

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-methyl-D-aspartate (NMDA) receptor signaling pathway can correct key neural dysfunctions in a mouse model of fragile X syndrome.

-甲基-D-天冬氨酸（NMDA）受体信号通路可以纠正脆性X综合征小鼠模型中的关键神经功能障碍。

The research, titled “

这项研究题为“

Non-ionotropic signaling through the NMDA receptor GluN2B carboxy-terminal domain drives dendritic spine plasticity and reverses fragile X phenotypes

通过NMDA受体GluN2B羧基末端结构域的非离子型信号传导驱动树突棘可塑性并逆转脆性X综合征表型

,” was published in

“，”出版于

Cell Reports

细胞报告

.

。

Led by Mark Bear, PhD, at MIT’s Picower Institute for Learning and Memory, the study builds on previous work by this group exploring the role of NMDA receptors in regulating synaptic plasticity. The group studies synaptic plasticity and has a history of exploring the molecular basis of fragile X syndrome, and a related disorder, tuberous sclerosis (Tsc)..

由麻省理工学院皮考尔学习与记忆研究所的马克·贝尔博士领导，这项研究建立在该小组先前工作的基础上，探索了NMDA受体在调节突触可塑性中的作用。该小组研究突触可塑性，并且有探索脆性X综合征及相关的结节性硬化症（Tsc）分子基础的历史。

Fragile X is characterized by excessive protein synthesis, which leads to synaptic dysfunction and predisposition to seizures, while Tsc involves reduced protein synthesis. In fact, crossbreeding mouse models of both conditions results in healthy offspring, with the protein expression levels balancing each other..

脆性X综合征的特征是蛋白质合成过多，这会导致突触功能障碍和癫痫发作的倾向，而Tsc则涉及蛋白质合成减少。事实上，将这两种病症的小鼠模型进行杂交后，其后代是健康的，因为蛋白质表达水平相互平衡。

NMDA receptors play a critical role in synaptic plasticity, where calcium ions flow through the receptor and contribute to long-term depression. More recent work from the group identified a signaling pathway for NMDA that was independent of ion flow.

NMDA受体在突触可塑性中起着关键作用，钙离子通过受体流动并有助于长期抑郁。该小组最近的研究确定了一种不依赖离子流动的NMDA信号通路。

The team hypothesized that two subunits of NMDA, GluN2A and GluN2B, have separate functions contributing to the two functional pathways, with GluN2A contributing to synaptic function via ion flow, while GluN2B modifies protein synthesis through the non-ionotropic mechanism.

该团队假设 NMDA 的两个亚基 GluN2A 和 GluN2B 具有分别贡献于两条功能通路的不同功能，其中 GluN2A 通过离子流影响突触功能，而 GluN2B 则通过非离子型机制调节蛋白质合成。

To test these hypotheses, the team used the shrinkage and enlargement of dendritic spines as a physical marker for synaptic plasticity in response to modifications in NMDA function. Knockout experiments showed that loss of either GluN2A or GluN2B disrupted long-term depression, a consequence of ionotropic signaling.

为了测试这些假设，研究团队使用树突棘的收缩和增大作为突触可塑性的物理标记，以响应NMDA功能的改变。敲除实验表明，GluN2A或GluN2B的缺失均破坏了由离子型信号传导引起的长期抑制。

Knocking out GluN2B eliminated spine shrinkage, a hallmark of synaptic plasticity through non-ionotropic signaling..

敲除GluN2B消除了脊柱收缩，这是通过非离子型信号传导的突触可塑性的标志。

The MIT researchers genetically engineered mice in which the carboxy-terminal domain (CTD) of GluN2B was swapped with that of GluN2A. They found that disrupting GluN2B’s CTD eliminated its ability to regulate spine size and increased bulk protein synthesis, mirroring what is seen in fragile X syndrome.

麻省理工学院的研究人员对小鼠进行了基因工程改造，将GluN2B的羧基末端结构域（CTD）与GluN2A的进行了交换。他们发现，破坏GluN2B的CTD消除了其调节脊柱大小的能力，并增加了整体蛋白质合成，这与脆性X综合征中观察到的情况相似。

Conversely, enhancing GluN2B signaling reduced protein synthesis to normal levels, similar to what is observed in Tsc models..

相反，增强GluN2B信号传导可将蛋白质合成降低至正常水平，这与Tsc模型中观察到的情况类似。

They then tested whether increasing GluN2B signaling could counteract fragile X-like phenotypes. Fragile X model mice were treated with Glyx-13, which selectively binds to GluN2B. Treatment normalized protein synthesis and reduced seizure susceptibility in fragile X model mice, suggesting that targeting GluN2B could represent a novel therapeutic approach for fragile X syndrome..

他们随后测试了增加GluN2B信号传导是否可以抵消类似脆性X综合征的表型。脆性X模型小鼠接受了选择性结合GluN2B的Glyx-13治疗。治疗使蛋白质合成正常化，并降低了脆性X模型小鼠的癫痫易感性，这表明靶向GluN2B可能代表了一种针对脆性X综合征的新治疗策略。

“These findings suggest that non-ionotropic NMDAR signaling through GluN2B may represent a novel therapeutic target for the treatment of fragile X and related causes of intellectual disability and autism,” the authors wrote.

“这些发现表明，通过GluN2B的非离子型NMDAR信号传导可能代表了治疗脆性X综合征及相关智力障碍和自闭症的新型治疗靶点，”作者写道。

By putting together data collected over decades, the MIT researchers identified a deeper understanding of a signaling pathway with broad implications for neurological disorders.

通过整合几十年来收集的数据，麻省理工学院的研究人员对一条信号通路有了更深入的理解，这对神经系统疾病有着广泛的影响。

“One of the things I find most satisfying about this study is that the pieces of the puzzle fit so nicely into what had come before,” said Bear.

“这项研究最让我感到满意的一点是，这些拼图碎片与之前的研究如此完美地契合在一起，”贝尔说。

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