Nature：破解自闭症谱系障碍的形成机制

自闭症谱系障碍（Autism spectrum disorder ，ASD）是一组以社交活动受限及交流障碍为特点的发育障碍性疾病，同时伴有行为受限、重复或呈刻板模式等特征。ADS是一种多基因控制的遗传疾病。Shank2编码兴奋性神经突触上的鹰架蛋白，最近的研究表明，人类Shank2突变与自闭症和智力障碍有关。

尽管随着科技进步越来越多与自闭症有关的基因被发现，但探索ASD发病机制与找到行之有效的治疗方法仍需要更多的努力。

本文中，研究者发现Shank2突变的小鼠也会表现出类似于人类自闭症的行为。包括社交活动较少、脑部超声波发射较少和焦虑等。这些小鼠显着缺乏N-甲基-天冬氨酸谷氨酸盐受体（N-methyld-aspartate glutamate receptor ，NMDAR）的活动。研究者用d-环丝氨酸，即NMDAR的激活剂直接刺激NMDAR,可以使Shank2突变小鼠的自闭症行为得到明显改善。

另外，研究者还尝试用亲代谢性谷氨酸盐受体5（metabotropic glutamate receptor 5 ，mGluR5）的变构调节剂增强NMDAR的功能，这种方法也能够改善Shank2突变小鼠的自闭症行为。

这一结果表明，NMDAR功能的弱化可能在Shank2突变小鼠的自闭症行为形成中起着关键作用。另外，mGluR对NMDARs的调节作用为ASD的治疗提供了潜在的策略。（生物谷 Bioon.com  ）

doi:10.1038/nature11208

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Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function

Hyejung Won, Hye-Ryeon Lee, Heon Yung Gee, Won Mah, Jae-Ick Kim, Jiseok Lee, Seungmin Ha, Changuk Chung, Eun Suk Jung, Yi Sul Cho, Sae-Geun Park, Jung-Soo Lee, Kyungmin Lee, Daesoo Kim, Yong Chul Bae, Bong-Kiun Kaang, Min Goo Lee & Eunjoon Kim

Autism spectrum disorder (ASD) is a group of conditions characterized by impaired social interaction and communication, and restricted and repetitive behaviours. ASD is a highly heritable disorder involving various genetic determinants1. Shank2 (also known as ProSAP1) is a multi-domain scaffolding protein and signalling adaptor enriched at excitatory neuronal synapses2, 3, 4, and mutations in the human SHANK2 gene have recently been associated with ASD and intellectual disablility5. Although ASD-associated genes are being increasingly identified and studied using various approaches, including mouse genetics6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, further efforts are required to delineate important causal mechanisms with the potential for therapeutic application. Here we show that Shank2-mutant (Shank2−/−) mice carrying a mutation identical to the ASD-associated microdeletion in the human SHANK2 gene exhibit ASD-like behaviours including reduced social interaction, reduced social communication by ultrasonic vocalizations, and repetitive jumping. These mice show a marked decrease in NMDA (N-methyl-d-aspartate) glutamate receptor (NMDAR) function. Direct stimulation of NMDARs with d-cycloserine, a partial agonist of NMDARs, normalizes NMDAR function and improves social interaction in Shank2−/− mice. Furthermore, treatment of Shank2−/− mice with a positive allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), which enhances NMDAR function via mGluR5 activation17, also normalizes NMDAR function and markedly enhances social interaction. These results suggest that reduced NMDAR function may contribute to the development of ASD-like phenotypes in Shank2−/− mice, and mGluR modulation of NMDARs offers a potential strategy to treat ASD.