FOXG1在皮层中间神经元亚群分化成熟中的作用及其调控机制

皮层中间神经元在神经环路中闸控着信息的传递和整合，其形态、电生理特征、分子标记物及功能各异，具有高度异质性,包含基本不交叉的三大亚群，即PV+、SST+和VIP+神经元。不同亚群的发育缺陷常导致多种脑高级功能障碍，疾病的临床症状亦不尽相同，但机制不明。我们前期利用Pv-Cre、Sst-Cre、Vip-Cre分别在不同亚群中敲除转录因子Foxg1，发现PV+神经元形成的突触数目减少，SST+神经元亚型分化异常，伴随着小鼠焦虑和社会交往能力的改变。本项目将在此基础上通过形态学和电生理手段明确Foxg1对三大亚群神经元分化成熟的调控以及对皮层神经环路兴奋性和抑制性平衡的影响;利用行为学手段比较分析不同亚群缺陷对小鼠行为的影响，进而解析FOXG1综合征认知和情感障碍、癫痫等症状的细胞机制；采用CHIP-Seq和RNA-Seq探讨其机制。本项目旨在理解各亚群的分化调控机制和各亚群在脑高级功能中的作用

Although only consisted of 20-30% in the cortex, GABAergic inhibitory interneurons play critical roles to gate signal flow and sculpt network dynamics. Cortical inhibitory interneurons are a highly heterogeneous population and consist of several subpopulations that exhibit distinct cellular properties, including specific morphologies, molecular profiles and electrophysiological properties. Developmental defects of interneurons often lead to cognitive and emotional defects as well as limitation of social ability. It has been demonstrated that the calcium-binding protein parvalbumin (PV), the neuropeptide somatostatin (SST), and the vesointestinal peptide (VIP) are expressed in largely non-overlapping subpopulations in the cortex. During development, most cortical interneurons are derived from the ganglionic eminence and tangentially migrate to the dorsal cortex. Subpopulations of PV+ and SST+ interneurons originate from the medial ganglionic eminence, while the VIP+ interneurons derives from the caudal ganglionic eminence. However, the mechanisms underlying subpopulation differentiation of interneurons remain unclear. In this study by conditional disruption of Foxg1 in distinct subpopulations achieved by crossing Pv-Cre, Sst-Cre, Vip-Cre with Foxg1fl/fl, respectively, we have found the number of inhibitory synapses is significantly reduced in Pv-Cre;Foxg1fl/fl mice, and the subtype specification of SST+ interneurons is affected in Sst-Cre;Foxg1fl/fl. Moreover the Pv-Cre;Foxg1fl/fl mice exhibit increased anxiety and abnormal social behaviours. Next, we will assess the effects of Foxg1 deletion on each subpopulation differentiation including morphological changes and their electrophysiological properties. Behavioural tests will be performed on Pv-Cre; Foxg1fl/fl, Sst-Cre; Foxg1fl/fl, and Vip-Cre;Foxg1fl/fl mice, respectively, to further compare the contributions of each distinct subpopulation to the cognitive, emotional and social abnormalities. CHIP-Seq and RNA-seq will be employed to explore downstream targets of Foxg1 to regulate the differentiation of subpopulation interneurons. Our study will put insights into the mechanisms of the development of cortical interneurons and FOXG1-related disorders.