MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders
MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders
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DOI：
10.7554/elife.20059
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发表时间：
2016-10-25
期刊：
影响因子：
7.7
通讯作者：
Cowan, Christopher W.
中科院分区：
文献类型：
--
作者：
Harrington, Adam J.;Raissi, Aram;Cowan, Christopher W.
与MEF2C相关的许多基因变异与自闭症、智力残疾(ID)和精神分裂症(SCZ)有关，SCZ是一种病理生理学不清楚的神经发育障碍的异质性集合。MEF2C在发育中的皮质兴奋性神经元中高表达，但其在神经元发育中的作用尚不清楚。我们在这里表明，有条件的胚胎缺失皮层和海马区兴奋性神经元(Emx1系)中的MEF2C会导致体内皮质网络活动的急剧减少，部分原因是抑制作用显著增加，兴奋性突触传递减少。此外，我们发现MEF2C主要作为细胞自主的转录抑制因子来调节E/I突触密度。对MEF2C突变皮层差异基因表达的分析发现，MEF2C突变小鼠与许多突触和自闭症相关基因存在显著重叠，并且MEF2C突变小鼠表现出许多令人想起自闭症、ID和SCZ的行为，这表明干扰新皮质中的MEF2C功能可以在小鼠中产生自闭症和ID样行为。
Numerous genetic variants associated with MEF2C are linked to autism, intellectual disability (ID) and schizophrenia (SCZ) a heterogeneous collection of neurodevelopmental disorders with unclear pathophysiology. MEF2C is highly expressed in developing cortical excitatory neurons, but its role in their development remains unclear. We show here that conditional embryonic deletion of Mef2c in cortical and hippocampal excitatory neurons (Emx1-lineage) produces a dramatic reduction in cortical network activity in vivo, due in part to a dramatic increase in inhibitory and a decrease in excitatory synaptic transmission. In addition, we find that MEF2C regulates E/I synapse density predominantly as a cell-autonomous, transcriptional repressor. Analysis of differential gene expression in Mef2c mutant cortex identified a significant overlap with numerous synapse- and autism-linked genes, and the Mef2c mutant mice displayed numerous behaviors reminiscent of autism, ID and SCZ, suggesting that perturbing MEF2C function in neocortex can produce autistic- and ID-like behaviors in mice.