Molecular Mechanisms Underlying the sex-Depended Maturation of Modulatory Systems.

项目摘要/摘要 男性被诊断为自闭症谱系障碍(ASD)的频率至少是女性的四倍，但 男性占主导地位的分子基础仍然难以捉摸。中缝核内的5-羟色胺能神经元 (RN)将轴突投射延伸到整个大脑，并调节许多基本的大脑功能，包括社会功能 行为。重要的是，ASD中已经描述了5-羟色胺系统的异常发育。5-羟色胺信号传导 在大脑中，男性和女性不同，但调节性别依赖的5-羟色胺突触的分子机制 功能在很大程度上是未知的。这项提议的首要目标是阐明分子机制。 性别依赖性5-羟色胺突触的发育和功能，并确定5-羟色胺的性别依赖性效应 通过关注跨突触分子神经氨酸(Nrxns)对社会行为的影响，Nrxns是一种公认的危险因素 治疗神经发育障碍，包括自闭症。 突触的形成和调节是大脑发育和发育中的基本生物学过程。 功能。这些事件需要跨突触的蛋白质-蛋白质相互作用来功能性地调节前和 决定突触功能的突触后结构。Neurexins(Nrxns)是突触前细胞黏附 分子，并通过跨突触蛋白相互作用参与突触的形成和调节 突触后黏附分子，如神经连接蛋白。重要的是，Nrxn和5-HT突变小鼠模型显示 使人联想到自闭症的社会认知行为缺陷。尽管有证据表明Synapse规范 依赖于Nrxn的功能以及适当的5-羟色胺信号影响社会认知行为，Nrxns的作用 在5-羟色胺中，Nrxn的突触传递和性别依赖性功能尚不清楚。 我们的中心假设是，5-羟色胺系统经历了性别特有的调节或发育。至 检验这一假说，我们将确定Nrxn蛋白是如何具体塑造5- 男性和女性的羟色胺系统。这将揭示一个以前从未探索过的5-HT系统架构，它形成了 5-羟色胺的神经传递和行为。我们将确定1)Nrxn基因(S)对性别依赖具有重要意义 5-羟色胺在RN和海马区释放的研究进展(目标1)Nrxn基因(S)与性别依赖有关 海马5-羟色胺系统结构的发展(目标2)，以及III)与性别有关的Nrxn基因(S)- 依赖社会行为(目标3)。 我们预计，我们对异常5-羟色胺信号的性别特异性后果的调查将深刻地 促进我们对特定性别行为的理解。因此，我们的工作应该有助于阐明 导致男性ASD患病率的分子机制以及确定新的治疗方法 目标是治疗神经发育和神经精神障碍(如ASD)的认知行为缺陷。

PROJECT SUMMARY/ABSTRACT Males are diagnosed with autism spectrum disorder (ASD) at least four times as frequently as females, but the molecular underpinnings of male predominance remain elusive. Serotonergic (5-HT) neurons in the raphe nuclei (RN) extend axonal projections throughout the brain and regulate many essential brain function, including social behaviors. Importantly, abnormal development of the 5-HT system has been described in ASD. 5-HT signaling in the brain differs in males and females, but molecular mechanisms regulating sex-dependent 5-HT synaptic function are largely unknown. The overarching goal of this proposal is to elucidate molecular mechanisms underlying sex-dependent 5-HT synapse development and function, and determine sex-dependent effects of 5- HT on social behavior by focusing on the trans-synaptic molecules Neurexins (Nrxns), a well-accepted risk factor for neurodevelopmental disorders, including ASD. The formation and regulation of synapses are fundamental biological processes in brain development and function. These events require trans-synaptic protein-protein interactions to functionally regulate pre- and postsynaptic structures that determine synaptic function. Neurexins (Nrxns) are presynaptic cell-adhesion molecules and involved in synapse formation and regulation through trans-synaptic protein interactions with postsynaptic adhesion molecules such as neuroligins. Importantly, Nrxn and 5-HT mutant mouse models display deficits in social cognitive behaviors which are reminiscent of ASD. Despite evidence that synapse specification relies on Nrxn function and that appropriate 5-HT signaling impacts social cognitive behaviors, the role of Nrxns in 5-HT synaptic transmission and sex-dependent Nrxn functions is unknown. Our central hypothesis is that the 5-HT system undergoes sex-specific modulation or development. To test this hypothesis, we will identify how Nrxn proteins specifically shape the development and function of the 5- HT system in males and females. This will reveal a previously unexplored 5-HT system architecture that shapes 5-HT neurotransmission and behavior. We will determine i) Nrxn gene(s) important for sex-dependent development of 5-HT release in the RN and hippocampus (Aim 1), ii) Nrxn gene(s) important for sex-dependent development of 5-HT system structure in the hippocampus (Aim 2), and iii) Nrxn gene(s) important for sex- dependent social behavior (Aim 3). We anticipate that our investigation of sex-specific consequences of abnormal 5-HT signaling will profoundly advance our understanding of sex-specific behaviors. Our work should thus contribute to the elucidation of the molecular mechanisms that contribute to the male prevalence of ASD, as well as identify novel therapeutic targets to treat cognitive behavioral deficits in neurodevelopmental and neuropsychiatric disorders such as ASD.