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

项目总结/摘要 男性被诊断患有自闭症谱系障碍（ASD）的频率至少是女性的四倍，但 男性优势的分子基础仍然难以捉摸。中缝核5-羟色胺能神经元 (RN)轴突投射延伸到整个大脑，并调节许多基本的大脑功能，包括社交功能。 行为。重要的是，5-HT系统的异常发育已在ASD中描述。5-HT信号传导 在大脑中，男性和女性不同，但调节性别依赖性5-HT突触的分子机制， 功能在很大程度上是未知的。这项建议的首要目标是阐明分子机制 潜在的性别依赖性5-HT突触的发育和功能，并确定5-HT的性别依赖性效应。 HT通过关注跨突触分子Neurexins（Nrxns）对社会行为的影响，这是一个公认的风险因素 包括自闭症在内的神经发育障碍 突触的形成和调节是大脑发育中的基本生物学过程， 功能这些事件需要跨突触蛋白质-蛋白质相互作用来功能性地调节突触前和突触后的蛋白质-蛋白质相互作用。 决定突触功能的突触后结构。神经毒素（Nrxns）是突触前细胞粘附 分子，并通过跨突触蛋白相互作用参与突触形成和调节， 突触后粘附分子，如神经连接素。重要的是，Nrxn和5-HT突变小鼠模型显示， 社交认知行为的缺陷让人联想到ASD。尽管有证据表明突触特化 依赖于Nrxn功能，适当的5-HT信号传导影响社会认知行为，Nrxns的作用 5-HT突触传递和性别依赖性Nrxn功能尚不清楚。 我们的中心假设是，5-HT系统进行性别特异性调制或发展。到 为了验证这一假设，我们将确定Nrxn蛋白如何特异性地塑造5- 雄性和雌性的HT系统。这将揭示一个以前未探索的5-HT系统架构， 5-HT神经传递和行为。我们将确定i）Nrxn基因对性别依赖性 RN和海马中5-HT释放的发展（目的1），ii）Nrxn基因对性别依赖性 海马体中5-HT系统结构的发育（目的2），和iii）Nrxn基因对性- 依赖性社会行为（目标3）。 我们预期，我们对异常5-HT信号传导的性别特异性后果的研究将深刻地 促进我们对性行为的理解。因此，我们的工作应有助于阐明 有助于ASD男性患病率的分子机制，以及确定新的治疗方法， 治疗神经发育和神经精神障碍（如ASD）中的认知行为缺陷。

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.