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Abstract：
UNASSIGNED: Heterozygous mutations or deletions of MEF2C cause a neurodevelopmental disorder termed MEF2C haploinsufficiency syndrome (MCHS), characterized by autism spectrum disorder and neurological symptoms. In mice, global Mef2c heterozygosity has produced multiple MCHS-like phenotypes. MEF2C is highly expressed in multiple cell types of the developing brain, including GABAergic (gamma-aminobutyric acidergic) inhibitory neurons, but the influence of MEF2C hypofunction in GABAergic neurons on MCHS-like phenotypes remains unclear.
UNASSIGNED: We employed GABAergic cell type-specific manipulations to study mouse Mef2c heterozygosity in a battery of MCHS-like behaviors. We also performed electroencephalography, single-cell transcriptomics, and patch-clamp electrophysiology and optogenetics to assess the impact of Mef2c haploinsufficiency on gene expression and prefrontal cortex microcircuits.
UNASSIGNED: Mef2c heterozygosity in developing GABAergic cells produced female-specific deficits in social preference and altered approach-avoidance behavior. In female, but not male, mice, we observed that Mef2c heterozygosity in developing GABAergic cells produced 1) differentially expressed genes in multiple cell types, including parvalbumin-expressing GABAergic neurons, 2) baseline and social-related frontocortical network activity alterations, and 3) reductions in parvalbumin cell intrinsic excitability and inhibitory synaptic transmission onto deep-layer pyramidal neurons.
UNASSIGNED: MEF2C hypofunction in female, but not male, developing GABAergic cells is important for typical sociability and approach-avoidance behaviors and normal parvalbumin inhibitory neuron function in the prefrontal cortex of mice. While there is no apparent sex bias in autism spectrum disorder symptoms of MCHS, our findings suggest that GABAergic cell-specific dysfunction in females with MCHS may contribute disproportionately to sociability symptoms.
UNASSIGNED: We employed GABAergic cell type-specific manipulations to study mouse Mef2c heterozygosity in a battery of MCHS-like behaviors. We also performed electroencephalography, single-cell transcriptomics, and patch-clamp electrophysiology and optogenetics to assess the impact of Mef2c haploinsufficiency on gene expression and prefrontal cortex microcircuits.
UNASSIGNED: Mef2c heterozygosity in developing GABAergic cells produced female-specific deficits in social preference and altered approach-avoidance behavior. In female, but not male, mice, we observed that Mef2c heterozygosity in developing GABAergic cells produced 1) differentially expressed genes in multiple cell types, including parvalbumin-expressing GABAergic neurons, 2) baseline and social-related frontocortical network activity alterations, and 3) reductions in parvalbumin cell intrinsic excitability and inhibitory synaptic transmission onto deep-layer pyramidal neurons.
UNASSIGNED: MEF2C hypofunction in female, but not male, developing GABAergic cells is important for typical sociability and approach-avoidance behaviors and normal parvalbumin inhibitory neuron function in the prefrontal cortex of mice. While there is no apparent sex bias in autism spectrum disorder symptoms of MCHS, our findings suggest that GABAergic cell-specific dysfunction in females with MCHS may contribute disproportionately to sociability symptoms.
摘要：
■MEF2C杂合突变或缺失导致神经发育障碍，称为MEF2C单倍功能不全综合征（MCHS），以自闭症谱系障碍和神经症状为特征。在老鼠身上,全球Mef2c杂合性产生了多个MCHS样表型。MEF2C在发育中的大脑的多种细胞类型中高度表达，包括GABA能（γ-氨基丁酸能）抑制性神经元，但是GABA能神经元中MEF2C功能减退对MCHS样表型的影响尚不清楚。
■我们采用GABA能细胞类型特异性操作来研究一系列MCHS样行为中的小鼠Mef2c杂合性。我们还做了脑电图检查,单细胞转录组学，和膜片钳电生理学和光遗传学，以评估Mef2c单倍体功能不全对基因表达和前额叶皮质微电路的影响。
■发育中的GABA能细胞中的Mef2c杂合性在社会偏好和回避行为方面产生了女性特异性缺陷。在女性中，但不是男性,老鼠,我们观察到发育中的GABA能细胞中的Mef2c杂合性产生1）在多种细胞类型中差异表达的基因，包括表达小白蛋白的GABA能神经元，2)基线和社交相关的额叶皮质网络活动改变，3）小清蛋白细胞内在兴奋性的降低和向深层锥体神经元的抑制性突触传递。
■女性MEF2C功能减退，但不是男性,发育中的GABA能细胞对于小鼠前额叶皮层的典型社交能力和回避行为以及正常的小清蛋白抑制性神经元功能很重要。虽然MCHS的自闭症谱系障碍症状没有明显的性别偏见，我们的研究结果表明,女性MCHS患者的GABA能细胞特异性功能障碍可能不成比例地导致社交性症状.
■我们采用GABA能细胞类型特异性操作来研究一系列MCHS样行为中的小鼠Mef2c杂合性。我们还做了脑电图检查,单细胞转录组学，和膜片钳电生理学和光遗传学，以评估Mef2c单倍体功能不全对基因表达和前额叶皮质微电路的影响。
■发育中的GABA能细胞中的Mef2c杂合性在社会偏好和回避行为方面产生了女性特异性缺陷。在女性中，但不是男性,老鼠,我们观察到发育中的GABA能细胞中的Mef2c杂合性产生1）在多种细胞类型中差异表达的基因，包括表达小白蛋白的GABA能神经元，2)基线和社交相关的额叶皮质网络活动改变，3）小清蛋白细胞内在兴奋性的降低和向深层锥体神经元的抑制性突触传递。
■女性MEF2C功能减退，但不是男性,发育中的GABA能细胞对于小鼠前额叶皮层的典型社交能力和回避行为以及正常的小清蛋白抑制性神经元功能很重要。虽然MCHS的自闭症谱系障碍症状没有明显的性别偏见，我们的研究结果表明,女性MCHS患者的GABA能细胞特异性功能障碍可能不成比例地导致社交性症状.
