Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice [bulk RNA]

SETD5, a gene linked to intellectual disability (ID) and autism spectrum disorder (ASD), is a member of the SET-domain family and encodes a putative histone methyltransferase (HMT). To date, the mechanism by which SETD5 haploinsufficiency causes ASD/ID remains an unanswered question. Setd5 is the highly conserved mouse homolog, and although the Setd5 null mouse is embryonic lethal, the heterozygote is viable. Morphological tracing and multi electrode array was used on cultured cortical neurons. MRI was conducted of adult mouse brains and immunohistochemistry of juvenile mouse brains. RNA-Seq was used to investigate gene expression in the developing cortex. Behavioral assays were conducted on adult mice. Setd5+/- cortical neurons displayed significantly reduced synaptic density and neuritic outgrowth in vitro, with corresponding decreases in network activity and synchrony by electrophysiology. A specific subpopulation of fetal Setd5+/- cortical neurons showed altered gene expression of neurodevelopment-related genes. Setd5+/- animals manifested several autism-like behaviors, including hyperactivity, cognitive deficit, and altered social interactions. Anatomical differences were observed in Setd5+/- adult brains, accompanied by a deficit of deep-layer cortical neurons in the developing brain. Our data converge on a picture of abnormal neurodevelopment driven by Setd5 haploinsufficiency, consistent with a highly penetrant risk factor. Bulk RNA-Seq of CD24+ CD45- neuronal cells isolated from E18.5 WT or SetD5 +/- mouse fetuses.SETD5是一种与智力障碍（intellectual disability, ID）和自闭症谱系障碍（autism spectrum disorder, ASD）相关的基因，隶属于SET结构域家族，编码一种推定的组蛋白甲基转移酶（histone methyltransferase, HMT）。截至目前，SETD5单倍体不足引发ASD/ID的具体分子机制仍未明确。Setd5是高度保守的小鼠同源基因，尽管纯合敲除的Setd5小鼠会出现胚胎致死表型，但杂合Setd5小鼠可正常存活。本研究采用形态学追踪技术与多电极阵列，对体外培养的皮层神经元展开检测；对成年小鼠脑部开展磁共振成像（magnetic resonance imaging, MRI）扫描，对幼年小鼠脑部实施免疫组织化学分析；通过RNA测序（RNA-Seq）探究发育中皮层的基因表达谱；同时对成年小鼠进行行为学实验。体外实验结果显示，Setd5+/-杂合皮层神经元的突触密度与神经突长出水平显著降低，电生理检测表明其神经元网络活动与同步性也相应下降。特定亚群的胚胎期Setd5+/-皮层神经元出现神经发育相关基因的表达异常。Setd5+/-小鼠表现出多种自闭症样行为，包括活动过度、认知缺陷以及社交互动模式改变。在Setd5+/-成年小鼠脑部可观察到解剖学差异，同时其发育阶段的脑部存在皮层深层神经元数量不足的缺陷。本研究数据共同表明，Setd5单倍体不足会驱动神经发育异常，这与SETD5作为高外显率风险因子的定位相符。本数据集包含从胚胎发育第18.5天（E18.5）的野生型（wild type, WT）或Setd5+/-小鼠胚胎中分离得到的CD24阳性、CD45阴性神经元细胞的批量RNA测序（bulk RNA-Seq）数据。