The role of Neurexin in serotonin synaptic function and social behavior

Neurexin 在血清素突触功能和社会行为中的作用

• 批准号: 10406277
• 负责人: Amy Cheung
• 金额: $ 1.22万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-11 至 2022-07-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406277
• 关键词: Address; Affect; Animal Model; Axon; Behavior; Behavioral; Binding; Brain; Breeding; Cell Adhesion Molecules; Cells; Child; Clinical; Complex; Copy Number Polymorphism; Data; Development; Disease; Electrophysiology (science); Excitatory Synapse; Exhibits; Fluorescent in Situ Hybridization; Foundations; Functional disorder; Genes; Genomics; Goals; Hippocampus (Brain); Human; Impairment; Individual; Inhibitory Synapse; Investigation; Knock-out; Knowledge; Learning; Lentivirus; Light; Literature; Measures; Mediating; Memory; Microdialysis; Molecular; Mus; Mutation; Neurodevelopmental Disorder; Neurons; Nucleus Accumbens; Pathogenesis; Pathologic; Pathology; Pharmaceutical Preparations; Physiological; Physiology; Predisposition; Presynaptic Terminals; Property; Protein Isoforms; Proteins; Regimen; Regulation; Reporting; Rewards; Role; Serotonin; Signal Transduction; Social Behavior; Social Controls; Social Interaction; Structure; Synapses; Synaptic Transmission; Testing; Therapeutic; Thinking; Variant; autism spectrum disorder; base; behavioral impairment; behavioral study; brain abnormalities; emotion regulation; experimental study; extracellular; flexibility; genetic manipulation; in vivo; individuals with autism spectrum disorder; interdisciplinary approach; memory recognition; mouse model; nerve supply; neural circuit; neuroregulation; neurotransmission; neurotransmitter release; new therapeutic target; novel; particle; patch clamp; postnatal; postsynaptic; preference; presynaptic; prevent; promoter; protein distribution; relating to nervous system; risk variant; social; social deficits; symptomatology; synaptic function; transgene expression

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.

项目概要/摘要 该提案的目标是检查血清素 (5-HT) 突触处的突触前神经毒素 (Nrxns) 如何 影响整个大脑的 5-HT 信号传导和社会行为。 证实 5-HT 在许多行为中的调节作用，包括社交行为、奖励、情绪 大脑 5-HT 水平和功能异常与自闭症有关。 虽然 5-HT 疗法经常用于治疗 ASD，但其改善效果参差不齐。 症状学需要进一步研究 5-HT 介导的病理学 有许多不同的基因促成。 自闭症谱系障碍 (ASD) 易感性和临床表现变异性增加，尤其是突触功能障碍。 突触兴奋和抑制的失调仍然是 ASD Nrxns 发病机制的一个标志。 突触前细胞粘附分子，其特征在于维持突触功能以实现适当的神经功能 从两个启动子（α和β）转录的三个Nrxn基因表达六个主要的Nrxn。 此外，自闭症谱系障碍 (ASD) 中也有 Nrxn1 和 Nrxn2 基因突变的报道。 在目前的文献中，鉴于异常的 Nrxn，Nrxns 在 5-HT 突触中的作用尚未得到研究。 和 5-HT 功能独立地导致信号病理学和社会行为障碍，这一点至关重要 了解 Nrxn 介导的 5-HT 神经传递如何参与潜在的病理机制 ASD 的核心缺陷。 在这里，我将探讨通过 Nrxns 介导的 5-HT 信号如何调节社会行为（目标 1）和 Nrxns 如何调节与社会行为相关的 5-HT 回路（目标 2）。 我的初步研究表明，5-HT 神经元中的三个 Nrxn 基因被选择性删除。 5-HT 突触 Nrxns 的丢失会损害社会认知记忆和社会奖励偏好。 在目标 1 中，我将确定海马体和伏核分别对这些行为至关重要。 5-HTergic Nrxns 是否对通过完成社交（和其他复杂）的社交行为至关重要 此外，我将使用 (i) 5-HT 探讨 (i) 是否以及 (ii) 5-HT 对于社会行为是必要的。 在社会行为研究之前增强 5-HT 功能的疗法和 (ii) 体内微透析来测量 在目标 2 中，我将进行小鼠繁殖和慢病毒救援。 确定特定 Nrxns 是否控制社会行为的方法。 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对 5-HT 突触功能中的 Nrxns 进行了仔细检查。 有必要对自闭症谱系障碍（ASD）的社会行为障碍提供新的认识。