Interneuron Synapses: In Vivo Chemicogenetic Proteomics to Discover Developmental Brain Disorder Etiologies

摘要： 发育性脑障碍（DBD），如自闭症，癫痫和精神分裂症，是神经系统疾病 与复杂的遗传病因有关。新出现的证据有力地表明，DBD源于 神经元突触驱动的神经回路兴奋和抑制之间的紊乱（E/I失衡） 异常，以及抑制性中间神经元功能障碍。有趣的是，对非典型突触结构的分析 和异常的中间神经元功能在很大程度上是独立进行的，主要是因为 分离和分析中间神经元突触不存在。未知的分子组成和 神经元间突触的调节是神经科学知识中的一个基本空白，这限制了神经元间突触调节的能力。 分析它们对DBD的功能贡献。为了解决这一关键障碍，我建议利用体内 化学遗传蛋白质组学（iBioID）方法首次绘制了两种最常见的突触蛋白质组， 流行的遗传定义的中间神经元亚型，小清蛋白（PV）和生长抑素（SST）神经元。我 中心假设是这些细胞中突触的分子组成是独特的，反映了它们的 与其他突触的形态学和生理学差异，如突触能树突棘。我 预测神经元间突触作为DBD遗传负担的重要节点，这将通过以下方式揭示： 发现它们的蛋白质组成和分子功能。 本项目的长期目标是阐明神经元间突触信号传导的机制， 确定潜在的新型神经精神治疗机制。这个项目的主要目的是解剖 疾病相关突触分子在PV和SST神经群中的功能作用。评估如何 这些候选蛋白质在每个突触环境中相互作用，将有助于确定各种DBD如何会聚 类似的表型输出，并提高临床治疗的疗效。 ! !

ABSTRACT: Developmental brain disorders (DBDs), such as autism, epilepsy, and schizophrenia, are neurological disorders associated with complex genetic etiologies. Emerging evidence strongly suggests that DBDs arise from disturbances between neural circuit excitation and inhibition (E/I imbalance), driven by neuronal synapse abnormalities, as well as inhibitory interneuron dysfunction. Interestingly, analyses of atypical synapse structure and aberrant interneuron function have largely been pursued independently, primarily because the tools to isolate and analyze interneuron synapses were non-existent. The unknown molecular composition and modulation of interneuron synapses is a fundamental gap in neuroscience knowledge, which limits the ability to analyze their functional contribution to DBDs. To address this critical barrier, I propose to utilize in vivo chemicogenetic proteomics (iBioID) approach to chart, for the first time, the synaptic proteomes of the two most prevalent genetically-defined interneuron subtypes, parvalbumin (PV) and somatostatin (SST) neurons. My central hypothesis is that the molecular composition of synapses in these cells is unique, reflecting their morphological and physiological differences from other synapses, such as the glutamatergic dendritic spine. I predict that interneuron synapses serve as important nodes of DBD genetic burden, which will be revealed by the discovery of their protein composition and molecular functions. The long-term goal of this project is to elucidate the mechanisms of interneuron synaptic signaling in order to identify potential novel neuropsychiatric treatment mechanisms. The primary objective of this project is to dissect the functional role of disease-relevant synaptic molecules in PV and SST neural populations. Evaluating how these candidate proteins interact in each synaptic environment will help determine how various DBDs converge on similar phenotypic outputs and improve the efficacy of clinical therapies. ! !