The role of Neurexin in serotonin synaptic function and social behavior

项目总结/摘要 本研究的目的是研究突触前神经毒素（Nrxns）如何在5-羟色胺（5-HT）突触 影响5-HT信号和社会行为。广泛的5-HT轴突终末神经支配整个大脑 证实了5-HT在许多行为中的调节作用，包括社会行为，奖励，情绪 调节，学习和记忆。大脑5-HT水平和功能异常与自闭症有关 谱系障碍（ASD）。虽然5-HT治疗剂通常用于治疗ASD，但在ASD的治疗中， 病理学需要进一步研究5-HT介导的病理学。许多不同的基因有助于 ASD易感性和临床表现变异性增加。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发病机制的标志。Nrxns是 突触前细胞粘附分子，其特征在于维持突触功能，以使适当的神经元 电路组装从两个启动子（α和β）转录的三个Nrxn基因表达六种主要的Nrxn 亚型（α Nrxn 1 -3，βNrxn 1-3）。此外，在ASD中已经报道了Nrxn 1和Nrxn 2基因的突变。 在目前的文献中，Nrxns在5-HT突触中的作用还有待研究。考虑到异常的Nrxn 和5-HT功能独立地导致信号病理学和社会行为障碍，这是至关重要的 了解Nrxn介导的5-HT神经传递如何参与病理机制， ASD的核心缺陷。 在这里，我将探讨如何通过Nrxns介导的5-HT信号调节社会行为（目标1）， Nrxns如何调节与社会行为相关的5-HT回路（目的2）。我们的团队创造了一种新的老鼠 在5-HT神经元中选择性删除三个Nrxn基因的模型。我的初步研究表明 5-HT突触Nrxns的缺失会损害社会识别记忆和社会奖励偏好。的 海马体和脑桥核分别在这些行为中至关重要。在目标1中，我将确定 5-HTergic Nrxns是否通过完成社交（和其他复杂）对社交行为至关重要 行为研究此外，我将探讨（i）如果和（ii）如何5-HT是必要的社会行为使用（i）5-HT 在社会行为研究之前增加5-HT功能的治疗和（ii）体内微透析以测量 细胞外5-羟色胺水平在社会行为。在目标2中，我将执行小鼠繁殖和慢病毒拯救 方法来确定特定的Nrxns是否控制社会行为。此外，我将使用 免疫组织化学和电生理学方法来鉴定Nrxn蛋白如何调节兴奋性和 抑制性突触分布和生理学。Nrxns在5-HT突触功能中的密切检查是 有必要对ASD的社会行为障碍进行新的阐述。

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.