Science：自闭症治疗新靶点

在儿童时期自闭症患者的大脑就会出现一些广泛性发育障碍（pervasive developmental disorder），瑞士巴塞尔大学的Peter Scheiffele和Kaspar Vogt教授近日在自闭症患者的大脑中发现并扭转了一个特定功能障碍的神经回路。这是一个有助于开发自闭症药物的研究，相关论文发表在Science杂志上。

据统计，大约百分之一的儿童可发生可归类为自闭症的障碍。自闭症是一种遗传性的大脑发育障碍疾病目前，目前尚无法治愈，行为治疗等也仅可缓解一些症状。已经发现自闭症患者有超过300个基因发生突变，其中包括神经连接蛋白-3（neuroligin-3）,它与突触的形成有关。

neuroligin-3基因缺失的小鼠表现出自闭症的一些症状。通过与罗氏合作，研究者发现，调节神经元之间信号传导的谷氨酸受体表达上升，导致了突触信号传导的异常，进而干扰了神经元回路的功能和可塑性，长此以往大脑的发育和功能受到影响。

若刺激neuroligin-3基因缺失小鼠neuroligin-3的表达，谷氨酸受体的表达便会降到正常水平，自闭症患者大脑中的缺陷结构也随之消失。因此，这些谷氨酸受体可以作为自闭症治疗的靶点，此项研究的科学家正和罗氏合作开发谷氨酸受体的拮抗剂。

编译自Scientists reverse disorder of neuronal circuits in autism

doi:10.1126/science.1224159
PMC:
PMID:

Shared Synaptic Pathophysiology in Syndromic and Nonsyndromic Rodent Models of Autism

Stéphane J. Baudouin1, Julien Gaudias1, Stefan Gerharz1,*, Laetitia Hatstatt1, Kuikui Zhou2, Pradeep Punnakkal1, Kenji F. Tanaka3,4, Will Spooren5, Rene Hen3, Chris I. De Zeeuw2,6, Kaspar Vogt1, Peter Scheiffele

The genetic heterogeneity of autism poses a major challenge for identifying mechanism-based treatments. A number of rare mutations are associated with autism, and it is unclear whether these result in common neuronal alterations. Monogenic syndromes, such as fragile X, include autism as one of their multifaceted symptoms and have revealed specific defects in synaptic plasticity. We discovered an unexpected convergence of synaptic pathophysiology in a nonsyndromic form of autism with those in fragile X syndrome. Neuroligin-3 knockout mice (a model for nonsyndromic autism) exhibited disrupted hetero-synaptic competition and perturbed metabotropic glutamate receptor-dependent synaptic plasticity, a hallmark of fragile X. These phenotypes could be rescued by re-expression of neuroligin-3 in juvenile mice, highlighting the possibility for reverting neuronal circuit alterations in autism after completion of development.