Altered Cortical Dynamics and Cognitive Function upon Haploinsufficiency of the Autism-Linked Excitatory Synaptic Suppressor MDGA2
Altered Cortical Dynamics and Cognitive Function upon Haploinsufficiency of the Autism-Linked Excitatory Synaptic Suppressor MDGA2
复制标题
DOI：
10.1016/j.neuron.2016.08.016
复制
发表时间：
2016-09-07
期刊：
影响因子：
16.2
通讯作者：
Craig, Ann Marie
中科院分区：
文献类型：
--
作者：
Connor, Steven A.;Ammendrup-Johnsen, Ina;Craig, Ann Marie
突触组织通路的突变导致自闭症。自闭症相关的MDGA2（含有糖基磷脂酰肌醇锚定2的MAM结构域）突变被认为可以减少兴奋性/抑制性传递。然而，我们发现Mdga2突变可提高兴奋性传递，Mdga2阻断神经素-1与神经素的相互作用，抑制兴奋性突触的发育。Mdga2（+/-）小鼠，模拟自闭症突变，显示不对称突触密度增加，mEPSC频率和振幅增加，LTP改变，而抑制性突触的测量没有变化。行为分析揭示了自闭症样表型，包括刻板印象、异常的社会互动和记忆受损。体内电压敏感染料成像，便于与自闭症的功能磁共振成像研究进行比较，揭示了皮层自发活动和皮质内功能连接的广泛增加。这些结果表明，MDGA2的突变通过兴奋升高和超连接的双重不利因素导致了皮质加工的改变，并表明NRXN-NLGN通路在正常情况下的任何方向的扰动都会增加自闭症的风险。
Mutations in a synaptic organizing pathway contribute to autism. Autism-associated mutations in MDGA2 (MAM domain containing glycosylphosphatidylinositol anchor 2) are thought to reduce excitatory/inhibitory transmission. However, we show that mutation of Mdga2 elevates excitatory transmission, and that MDGA2 blocks neuroligin-1 interaction with neurexins and suppresses excitatory synapse development. Mdga2(+/-) mice, modeling autism mutations, demonstrated increased asymmetric synapse density, mEPSC frequency and amplitude, and altered LTP, with no change in measures of inhibitory synapses. Behavioral assays revealed an autism-like phenotype including stereotypy, aberrant social interactions, and impaired memory. In vivo voltage-sensitive dye imaging, facilitating comparison with fMRI studies in autism, revealed widespread increases in cortical spontaneous activity and intracortical functional connectivity. These results suggest that mutations in MDGA2 contribute to altered cortical processing through the dual disadvantages of elevated excitation and hyperconnectivity, and indicate that perturbations of the NRXN-NLGN pathway in either direction from the norm increase risk for autism.