Men1突变（G503D）以及Men1缺失导致中间神经元功能紊乱在抑郁发生发展中的作用机制研究

抑郁症是严重威胁人类健康的精神疾病，环境和遗传因素共同导致了抑郁的发生发展，但目前抑郁的遗传实验证据还相对缺乏。我们通过抑郁病人基因测序发现MEN1基因（蛋白menin）503位氨基酸的突变(G503D)和抑郁发生密切相关。为了从遗传角度深入探讨抑郁的发生机理，我们建立了menin（G503D）knock-in小鼠。发现该小鼠表现出可遗传的抑郁表型，以及PV表达增多。通过构建多种中间神经元敲除Men1的小鼠，证实了在PV神经元中敲除menin后也可导致小鼠抑郁表型。基于这些发现和小鼠模型，我们将结合AAV病毒注射、动物行为学、电生理、神经元形态、基因表观调控等方法，详细阐述menin突变和缺失调控中间神经元功能及在抑郁中的作用与机制。该研究不仅可以丰富抑郁基因突变的遗传基础，深入理解menin调控抑郁的发生机理；还可以为抑郁的早期诊断、个体化治疗、药物临床转化提供可能的治疗靶点和理论依据。

Major depressive disorder (MDD) is the most common recurring psychiatric illness in the world, which brings heavy spiritual and financial burden to society. It is now the first leading cause of disability worldwide and a major contributor to early mortality from suicide. . The etiology and development of depression are influenced by both environmental and genetic factors. Although there is strong evidence to support the involvement of genetic factors in MDD, efforts to elucidate biological mechanisms have not been successful. MEN1 (mice: men1) is a pathogenic gene of multiple endocrine neoplasm type 1 syndrome. Its coding protein, menin, interacts with a large number of transcription factors and directly participates in epigenetic regulation. In our previous works, we indicated that carriers of the MEN1 SNP rs375804228 (G503D), a risk variant, was associated with a higher risk of MDD onset. By constructing the corresponding point mutation mice, the G503D mice showed depression-like phenotype after more than ten generations and an increased expression of parvalbumin. Thus, we constructed the men1 conditional knockout mice in PV interneurons and found that PcKO mice also showed depressive-like phenotype and an increased PV expression. We copulated PcKO and control mice with Ai14 TD tomato cre reporter mice to obtain 1-month-old off spring mice whose PV neurons with FITC fluorescence. Single cell suspensions of adult PcKO and control mice brain were separated. Then flow cytometry was used to isolate PV neurons of PcKO mice and control mice. Isolated RNA of PV neurons was subsequently used for transcriptomics analysis. It’s found that the differentially expressed genes (DEGs) were closely related to the development of neurons. We identified that men1 deletion in CNS can lead to disparity in inhibitory neuron proliferation, which in turn leads to depression. Next，we found that the expression level of H3K27me3 increased after men1 deletion. The results of transcriptomics also indicated the change of epigenetic regulation. Based on that, we speculated that menin deletion may lead to the decrease of H3K27 trimethylation. The reduced methylated H3K27 resulted in loss of inhibition of Pvalb transcription.. The purpose of this study is to elucidate the role of menin mutation or deletion in depression and to provide possible therapeutic targets, biological indicators for the early diagnosis and treatment of depression.