The role of Neurexin in serotonin synaptic function and social behavior

项目摘要/摘要 这项提议的目标是研究突触前5-羟色胺(5-羟色胺)突触前神经氨酸(Nrxns)是如何 影响5-羟色胺信号和社会行为。脑内广泛的5-羟色胺轴突终末神经支配 证实了5-羟色胺在许多行为中的调节作用，包括社交行为、奖励、情绪 调节、学习和记忆。自闭症与脑内5-羟色胺水平和功能异常有关 频谱障碍(ASD)。虽然5-羟色胺疗法经常用于治疗ASD，但在 症状学要求进一步研究5-羟色胺介导的病理学。许多不同的基因对 ASD易感性增加，临床表现多变性。值得注意的是，突触功能障碍，特别是 突触兴奋和抑制的失调，仍然是ASD发病机制的一个标志。Nrxn是 突触前细胞黏附分子在维持正常神经突触功能方面有很好的特征 电路组件。由两个启动子(α和β)转录的三个nrxn基因表达六个主要的nrxn 亚型(αNrxn1-3，βNrxn1-3)。此外，已有报道在ASD中发现NRXN1和Nrxn2基因突变。 在目前的文献中，Nrxns在5-羟色胺突触中的作用尚未被研究。鉴于这一异常的Nrxn 而5-羟色胺功能独立地促进信号病理和社会行为障碍，这是至关重要的 了解Nrxn介导的5-羟色胺神经递质如何参与相关的病理机制 ASD的核心缺陷。 在这里，我将探索5-羟色胺信号如何通过Nrxns调节社会行为(目标1)和 Nrxns如何调节与社会行为相关的5-羟色胺回路(目标2)。我们团队创造了一种新的鼠标 5-羟色胺神经元中三个Nrxn基因选择性缺失的模型。我的初步研究表明 5-羟色胺突触中Nrxns的缺失会损害社会识别、记忆和社会奖赏偏好。这个 在这些行为中，海马体和伏隔核分别是至关重要的。在目标1中，我将确定 5-HTeric Nrxn是否通过完成社交(和其他情结)对社交行为至关重要 行为研究。此外，我将探讨(I)是否以及(Ii)5-HT对于使用5-HT的社会行为是必要的 在社会行为研究之前增加5-羟色胺功能的治疗和(Ii)体内微透析测量 社会行为过程中的细胞外5-羟色胺水平。在目标2中，我将进行一次小鼠繁殖和慢病毒救援 确定特定Nrxn是否控制社会行为的方法。此外，我将使用 免疫组织化学和电生理方法鉴定Nrxn蛋白如何调节兴奋性和 抑制性突触的分布和生理学。Nrxns在5-羟色胺突触功能中的仔细研究 有必要对自闭症的社会行为障碍有新的认识。

PROJECT SUMMARY/ABSTRACT The goal of this proposal is to examine how presynaptic Neurexins (Nrxns) at serotonin (5-HT) synapses impact 5-HT signaling and social behavior. Extensive 5-HT axon terminal innervation throughout the brain corroborates 5-HT’s modulatory role in numerous behaviors including social behaviors, reward, emotion regulation, and learning and memory. Abnormal brain 5-HT levels and function are implicated in Autism Spectrum Disorder (ASD). While 5-HT therapeutics are often used to treat ASD, variable improvements in symptomatology require further investigation of 5-HT-mediated pathology. Many different genes contribute to increased ASD susceptibility and clinical presentation variability. Notably, synaptic dysfunction, specifically dysregulation of synaptic excitation and inhibition, remains a hallmark of ASD pathogenesis. Nrxns are presynaptic cell adhesion molecules that are well characterized in maintaining synapse function for proper neural circuit assembly. The three Nrxn genes transcribed from two promoters (α and β) express six principal Nrxn isoforms (αNrxn1-3, βNrxn 1-3). Additionally, mutations in Nrxn1 and Nrxn2 genes have been reported in ASD. In the current literature, the role of Nrxns at 5-HT synapses has yet to be investigated. Given that aberrant Nrxn and 5-HT function independently contribute to signaling pathology and social behavior impairments, it is critical to understand how Nrxn-mediated 5-HT neurotransmission participates in pathological mechanisms underlying the core deficits of ASD. Here, I will explore how 5-HT signaling mediated through Nrxns regulates social behaviors (Aim 1) and how Nrxns regulate 5-HT circuits relevant to social behaviors (Aim 2). Our group has created a novel mouse model in which the three Nrxn genes are selectively deleted in 5-HT neurons. My preliminary studies indicate that the loss of Nrxns at 5-HT synapses impairs social recognition memory and social reward preference. The hippocampus and nucleus accumbens, respectively, are crucial in these behaviors. In Aim 1, I will determine whether 5-HTergic Nrxns are critical for social behaviors through completion of social (and other complex) behavior studies. In addition, I will explore (i) if and (ii) how 5-HT is necessary for social behaviors using (i) 5-HT therapeutics to augment 5-HT function prior to social behavior studies and (ii) in vivo microdialysis to measure extracellular 5-HT levels during social behavior. In Aim 2, I will perform a mouse breeding and lentiviral rescue approach to determine whether specific Nrxns control social behavior. Furthermore, I will use immunohistochemical and electrophysiological approaches to identity how Nrxn proteins regulate excitatory and inhibitory synapse distribution and physiology. A close examination of Nrxns in 5-HT synaptic function is necessary to shed new light on social behavior disturbances in ASD.