BACKGROUND Microdeletions of the MEF2C gene are linked to a syndromic form of autism termed MEF2C haploinsufficiency syndrome (MCHS). MEF2C hypofunction in neurons is presumed to underlie most of the symptoms of MCHS. However, it is unclear in which cell populations MEF2C functions to regulate neurotypical development. METHODS Multiple biochemical, molecular, electrophysiological, behavioral, and transgenic mouse approaches were used to characterize MCHS-relevant synaptic, behavioral, and gene expression changes in mouse models of MCHS. RESULTS We showed that MCHS-associated missense mutations cluster in the conserved DNA binding domain and disrupt MEF2C DNA binding. DNA binding-deficient global Mef2c heterozygous mice (Mef2c-Het) displayed numerous MCHS-related behaviors, including autism-related behaviors, changes in cortical gene expression, and deficits in cortical excitatory synaptic transmission. We detected hundreds of dysregulated genes in Mef2c-Het cortex, including significant enrichments of autism risk and excitatory neuron genes. In addition, we observed an enrichment of upregulated microglial genes, but this was not due to neuroinflammation in the Mef2c-Het cortex. Importantly, conditional Mef2c heterozygosity in forebrain excitatory neurons reproduced a subset of the Mef2c-Het phenotypes, while conditional Mef2c heterozygosity in microglia reproduced social deficits and repetitive behavior. CONCLUSIONS Taken together, our findings show that mutations found in individuals with MCHS disrupt the DNA-binding function of MEF2C, and DNA binding-deficient Mef2c global heterozygous mice display numerous MCHS-related phenotypes, including excitatory neuron and microglia gene expression changes. Our findings suggest that MEF2C regulates typical brain development and function through multiple cell types, including excitatory neuronal and neuroimmune populations.

中文翻译：

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神经元和神经免疫群体中的 MEF2C 功能减退在小鼠中产生 MEF2C 单倍剂量不足综合征样行为

背景技术 MEF2C 基因的微缺失与称为 MEF2C 单倍剂量不足综合征 (MCHS) 的自闭症综合征形式有关。神经元中的 MEF2C 功能减退被认为是 MCHS 大部分症状的基础。然而，尚不清楚 MEF2C 在哪些细胞群中发挥调节神经典型发育的作用。方法 使用多种生化、分子、电生理、行为和转基因小鼠方法来表征 MCHS 小鼠模型中 MCHS 相关的突触、行为和基因表达变化。结果 我们发现 MCHS 相关的错义突变聚集在保守的 DNA 结合域中并破坏 MEF2C DNA 结合。DNA 结合缺陷的全局 Mef2c 杂合子小鼠 (Mef2c-Het) 表现出许多与 MCHS 相关的行为，包括自闭症相关行为、皮质基因表达的变化、和皮质兴奋性突触传递的缺陷。我们在 Mef2c-Het 皮质中检测到数百个失调的基因，包括自闭症风险和兴奋性神经元基因的显着富集。此外，我们观察到上调的小胶质细胞基因富集，但这不是由于 Mef2c-Het 皮质中的神经炎症。重要的是，前脑兴奋性神经元中的条件性 Mef2c 杂合性再现了 Mef2c-Het 表型的一个子集，而小胶质细胞中的条件性 Mef2c 杂合性再现了社会缺陷和重复行为。结论 综上所述，我们的研究结果表明，在患有 MCHS 的个体中发现的突变破坏了 MEF2C 的 DNA 结合功能，并且 DNA 结合缺陷的 Mef2c 全局杂合小鼠显示出许多 MCHS 相关表型，包括兴奋性神经元和小胶质细胞基因表达的变化。我们的研究结果表明，MEF2C 通过多种细胞类型（包括兴奋性神经元和神经免疫细胞群）调节典型的大脑发育和功能。