AbstractRepetitive stereotyped behaviors are core symptoms of autism spectrum disorders (ASD) and fragile X syndrome (FXS), the prevalent genetic cause of intellectual disability and autism. The nigrostriatal dopamine (DA) circuit rules movement and creation of habits and sequential behaviors; therefore, its dysregulation could promote autistic repetitive behaviors.

摘要重复刻板行为是自闭症谱系障碍（ASD）和脆性X综合征（FXS）的核心症状，这是智力残疾和自闭症的普遍遗传原因。黑质纹状体多巴胺（DA）回路控制运动以及习惯和顺序行为的产生；因此，其失调可能会促进自闭症的重复行为。

Nevertheless, inspection of substantia nigra pars compacta (SNpc) DA neurons in ASD models has been overlooked and specific evidence of their altered activity in ASD and FXS is absent. Here, we show that hyperactivity of SNpc DA neurons is an early feature of FXS. The underlying mechanism relies on an interplay between metabotropic glutamate receptor 1 (mGluR1) and ErbB tyrosine kinases, receptors for the neurotrophic and differentiation factors known as neuregulins.

然而，在ASD模型中对黑质致密部（SNpc）DA神经元的检查被忽视，并且缺乏其在ASD和FXS中活性改变的具体证据。在这里，我们表明SNpc DA神经元的过度活跃是FXS的早期特征。潜在的机制依赖于代谢型谷氨酸受体1（mGluR1）和ErbB酪氨酸激酶之间的相互作用，ErbB酪氨酸激酶是神经营养和分化因子的受体，称为神经调节蛋白。

Up-regulation of ErbB4 and ErbB2 in nigral DA neurons drives neuronal hyperactivity and repetitive behaviors of the FXS mouse, concurrently rescued by ErbB inhibition. In conclusion, beyond providing the first evidence that nigral DA neuron hyperactivity is a signature of FXS and nigral mGluR1 and ErbB4/2 play a relevant role in FXS etiology, we demonstrate that inhibiting ErbB is a valuable pharmacological approach to attenuate stereotyped repetitive behaviors, thus opening an avenue toward innovative therapies for ASD and FXS treatment..

黑质DA神经元中ErbB4和ErbB2的上调驱动FXS小鼠的神经元过度活跃和重复行为，同时通过ErbB抑制来挽救。总之，除了提供第一个证据表明黑质DA神经元过度活跃是FXS的标志，黑质mGluR1和ErbB4/2在FXS病因学中起相关作用外，我们还证明抑制ErbB是一种有价值的药理学方法，可以减轻刻板的重复行为，从而为ASD和FXS治疗的创新疗法开辟了一条途径。。

IntroductionRepetitive behaviors, such as stereotyped movements, repetitive objects handling, and self-injurious behaviors, are core diagnostic signs of autism spectrum disorders (ASD), also overt in fragile X syndrome (FXS), the main genetic cause of autism and intellectual disability caused by Fmr1 silencing and loss of Fragile X Messenger Ribonucleoprotein (FMRP) [1,2,3].

。

The nigrostriatal dopamine (DA) circuit, arising from DA neurons of the substantia nigra pars compacta (SNpc), is key to movement control and the creation of habits and sequential behaviors [4, 5]; thus, its dysregulation is posited as a leading substrate of abnormal movements and restricted routines, emerging as compulsive and stereotyped behaviors in patients with ASD and FXS.

黑质纹状体多巴胺（DA）回路由黑质致密部（SNpc）的DA神经元产生，是运动控制和习惯和顺序行为产生的关键[4，5]；因此，其失调被认为是异常运动和限制性日常活动的主要基础，在ASD和FXS患者中表现为强迫和刻板行为。

Earlier clues about the role of the SNpc DA nucleus in repetitive behaviors stand up from evidence that pharmacological and genetic manipulations increasing striatal DA transmission in rodents promote stereotyped movements by striatal D1 activation [6,7,8,9,10,11]. The latest demonstration that optogenetic activation of SNpc DA neurons triggers self-grooming (a repetitive behavior) in mice [12] and self-grooming is attenuated by optogenetic inhibition of the SNpc-to-ventromedial striatum circuit [13] has strengthened the idea that hyperactivation of the nigrostriatal DA circuit is instrumental for repetitive behaviors.

关于SNpc DA核在重复行为中的作用的早期线索来自证据，即增加啮齿动物纹状体DA传递的药理学和遗传操作通过纹状体D1激活促进刻板运动[6,7,8,9,10,11]。最新的证据表明，SNpc DA神经元的光遗传激活触发了小鼠的自我修饰（一种重复行为），并且通过SNpc对腹内侧纹状体回路的光遗传抑制减弱了自我修饰，这强化了黑质纹状体DA回路的过度激活有助于重复行为的观点。

However, so far, precise evidence proving altered activity of nigral DA neuron in ASD or FXS models is absent, keeping the involvement of the SNpc DA nucleus in abnormal repetitive behaviors in ASD still rather theoretical [14,15,16,17].Striatal dysfunctions have been recently reported in the Fmr1 KO mouse, a validated model for FXS [18, 19].

然而，到目前为止，还没有确切的证据证明ASD或FXS模型中黑质DA神经元的活性发生了改变，因此SNpc DA核参与ASD异常重复行为仍然是理论上的[14,15,16,17]。最近在Fmr1 KO小鼠中报道了纹状体功能障碍，Fmr1 KO小鼠是FXS的验证模型[18，19]。

Few other studies described histological and neurochemical DA altera.

很少有其他研究描述组织学和神经化学DA altera。

Data availability

数据可用性

Source data generated in the current study are available from the corresponding author on reasonable request. Supplementary information is available at MP’s website.

当前研究中生成的源数据可根据合理要求从通讯作者处获得。。

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Download referencesAcknowledgementsThis work was partially supported by Il Fulcro Foundation (AL) and MNESYS (PE0000006)—A Multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022) (AL, NBM, CB). CB group work was also supported by Telethon Foundation GGP20137, PRIN 20227JA8R3 MUR Next Generation EU and SNSF 310030—215706.Author informationAuthors and AffiliationsDepartment of Experimental Neuroscience, Santa Lucia Foundation IRCCS, Rome, ItalySebastian L.

下载参考文献致谢这项工作得到了Il-Fulcro基金会（AL）和MNESYS（PE0000006）的部分支持，这是一种多尺度综合方法，用于研究健康和疾病中的神经系统（DN。1553 11.10.2022）（AL，NBM，CB）。CB小组的工作也得到了Telethon基金会GGP20137，PRIN 20227JA8R3 MUR下一代欧盟和SNSF 310030-215706的支持。作者信息作者和附属机构圣卢西亚基金会IRCCS实验神经科学系，罗马，意大利伊斯巴斯蒂安L。

D’Addario, Mariangela Massaro Cenere, Nicola B. Mercuri & Ada LedonneDepartment of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, ItalyEleonora Rosina & Claudia BagniDepartment of Fundamental Neurosciences, University of Lausanne, Lausanne, SwitzerlandClaudia BagniNeurology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, ItalyNicola B.

D'Addario，Mariangela Massaro Cenere，Nicola B.Mercuri＆Ada LedonneRome Tor Vergata大学生物医学与预防系，Italyelonora Rosina＆Claudia Bagnide洛桑大学洛桑分校基础神经科学系，Switzerlandcraudia BagniNeurology Unit，罗马Tor Vergata大学系统医学系，ItalyNicola B。

MercuriPharmacology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, ItalyAda LedonneAuthorsSebastian L. D’AddarioView author publicationsYou can also search for this author in.

罗马大学系统医学系MercuriPharmacology部门，罗马托尔维加塔，意大利莱顿作者Sebastian L.D'AddarioView作者出版物您也可以在中搜索这位作者。

PubMed Google ScholarEleonora RosinaView author publicationsYou can also search for this author in

PubMed Google ScholareLeonoraRosinaview作者出版物您也可以在

PubMed Google ScholarMariangela Massaro CenereView author publicationsYou can also search for this author in

PubMed Google ScholarMariangela Massaro CenereView作者出版物您也可以在

PubMed Google ScholarClaudia BagniView author publicationsYou can also search for this author in

PubMed Google ScholarClaudia BagniView作者出版物您也可以在

PubMed Google ScholarNicola B. MercuriView author publicationsYou can also search for this author in

PubMed Google ScholarNicola B.MercuriView作者出版物您也可以在

PubMed Google ScholarAda LedonneView author publicationsYou can also search for this author in

PubMed Google ScholarAda LedonneView作者出版物您也可以在

PubMed Google ScholarContributionsSLD performed mouse surgeries and intracerebral drug injections; performed and analyzed behavioral experiments. ER performed and analyzed western blot experiments. MMC performed and analyzed immunofluorescence experiments. CB supervised western blot experiments.

PubMed谷歌学术贡献SLD进行了小鼠手术和脑内药物注射；进行并分析了行为实验。ER进行并分析了蛋白质印迹实验。MMC进行并分析了免疫荧光实验。CB监督蛋白质印迹实验。

NBM provided devices and resources. AL conceived the project, designed the experiments, performed and analyzed all electrophysiological recordings, dissected brain samples for western blot and immunofluorescence experiments, supervised the project, prepared the figures, and wrote the manuscript. All authors discussed the results, commented on the manuscript and approved the final version.Corresponding authorCorrespondence to.

NBM提供了设备和资源。AL构思了该项目，设计了实验，执行并分析了所有电生理记录，解剖了用于蛋白质印迹和免疫荧光实验的大脑样本，监督了该项目，准备了数字并撰写了手稿。所有作者都讨论了结果，评论了手稿并批准了最终版本。对应作者对应。

Ada Ledonne.Ethics declarations

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Reprints and permissionsAbout this articleCite this articleD’Addario, S.L., Rosina, E., Massaro Cenere, M. et al. ErbB inhibition rescues nigral dopamine neuron hyperactivity and repetitive behaviors in a mouse model of fragile X syndrome.

转载和许可本文引用本文D'Addario，S.L.，Rosina，E.，Massaro-Cenere，M。等人。ErbB抑制可挽救脆性X综合征小鼠模型中的黑质多巴胺神经元过度活跃和重复行为。

Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02831-yDownload citationReceived: 16 April 2024Revised: 02 November 2024Accepted: 05 November 2024Published: 15 November 2024DOI: https://doi.org/10.1038/s41380-024-02831-yShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

摩尔精神病学（2024）。https://doi.org/10.1038/s41380-024-02831-yDownload引文收到日期：2024年4月16日修订日期：2024年11月2日接受日期：2024年11月5日发布日期：2024年11月15日OI：https://doi.org/10.1038/s41380-024-02831-yShare本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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Autism spectrum disordersNeuroscience

自闭症谱系障碍神经科学