Table_1_NMDARs Drive the Expression of Neuropsychiatric Disorder Risk Genes Within GABAergic Interneuron Subtypes in the Juvenile Brain.XLSX

Medial ganglionic eminence (MGE)-derived parvalbumin (PV)+, somatostatin (SST)+and Neurogliaform (NGFC)-type cortical and hippocampal interneurons, have distinct molecular, anatomical, and physiological properties. However, the molecular mechanisms regulating their maturation remain poorly understood. Here, via single-cell transcriptomics, we show that the obligate NMDA-type glutamate receptor (NMDAR) subunit gene Grin1 mediates transcriptional regulation of gene expression in specific subtypes of MGE-derived interneurons, leading to altered subtype abundances. Notably, MGE-specific early developmental Grin1 loss results in a broad downregulation of diverse transcriptional, synaptogenic and membrane excitability regulatory programs in the juvenile brain. These widespread gene expression abnormalities mirror aberrations that are typically associated with neurodevelopmental disorders. Our study hence provides a road map for the systematic examination of NMDAR signaling in interneuron subtypes, revealing potential MGE-specific genetic targets that could instruct future therapies of psychiatric disorders.

内侧神经节隆起（Medial ganglionic eminence, MGE）来源的小白蛋白（parvalbumin, PV）阳性、生长抑素（somatostatin, SST）阳性及神经胶质形（Neurogliaform, NGFC）型皮层与海马中间神经元，具有独特的分子、解剖与生理特性。然而，调控此类神经元成熟的分子机制目前仍不甚明晰。本研究通过单细胞转录组学分析，发现必需型N-甲基-D-天冬氨酸型谷氨酸受体（NMDA-type glutamate receptor, NMDAR）亚基基因Grin1可介导MGE来源特定中间神经元亚型的转录调控，进而改变其亚型丰度。值得注意的是，在MGE特异性早期发育阶段缺失Grin1，会广泛下调幼年大脑中多种转录、突触发生及膜兴奋性调控程序的表达。上述广泛的基因表达异常，与神经发育障碍通常伴随的畸变特征高度相似。因此，本研究为系统性探究中间神经元亚型中的NMDAR信号通路提供了研究路线图，并揭示了潜在的MGE特异性遗传靶点，可为未来精神疾病的治疗提供理论指导。