Single cell transcriptomic data from MGE-derived interneurons purified from postnatal day 18-21 frontal cortex and hippocampus of wild type and MGE-specific GRIN1-knockout mice.. Single cell transcriptomic data from MGE-derived interneurons purified from postnatal day 18-21 frontal cortex and hippocampus of wild type and MGE-specific GRIN1-knockout mice.

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 diversity remain poorly understood. Here, via single-cell transcriptomics, we show that the obligate NMDA-type glutamate receptor (NMDAR) subunit gene Grin1 mediates subtype-specific transcriptional regulation of gene expression in MGE-derived interneurons, leading to altered subtype identities. Notably, MGE-specific conditional Grin1 loss results in a systemic downregulation of diverse transcriptional, synaptogenic and membrane excitability regulatory programs. These widespread gene expression abnormalities mirror aberrations that are typically associated with neurodevelopmental disorders, particularly schizophrenia. Our study hence provides a roadmap for the systematic examination of NMDAR signaling in interneuron subtypes, revealing potential MGE-specific genetic targets that could instruct future therapies of psychiatric disorders. Overall design: Frontal cortex and hippocampus of wild-type and MGE-specific GRIN1-knockout mice have been dissected and FACS-sorted Nkx2.1-cell-type specific cells (Td-tomato positive)

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，具备独特的分子、解剖学及生理学特性。然而，调控此类神经元多样性的分子机制目前仍所知甚少。本研究借助单细胞转录组学（single-cell transcriptomics）技术，证实必需型NMDA型谷氨酸受体（NMDA-type glutamate receptor, NMDAR）亚基基因Grin1可介导MGE来源中间神经元的亚型特异性基因转录调控，进而改变神经元亚型身份。值得注意的是，MGE特异性条件性Grin1缺失会导致多种转录、突触发生及膜兴奋性调控程序出现系统性下调。这些广泛的基因表达异常与通常伴随神经发育障碍（尤其是精神分裂症）的紊乱特征高度相似。因此，本研究为系统性解析中间神经元亚型中的NMDAR信号通路提供了研究框架，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指导。总体设计：已解剖野生型及MGE特异性GRIN1敲除小鼠的前额叶皮层与海马体，并通过荧光激活细胞分选（Fluorescence-activated cell sorting, FACS）分离得到Nkx2.1细胞类型特异性的Td-番茄阳性细胞。