Resolving the impact of a human KCNQ3 mutation on mesostriatal dopamine connectivity and striatal network dynamics in social behavior

解决人类 KCNQ3 突变对社会行为中纹状体多巴胺连接和纹状体网络动态的影响

• 批准号: 10594900
• 负责人: Christopher W. Tschumi
• 金额: $ 5.69万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10594900
• 关键词: Action Potentials; Acute; Arginine; Behavior; Behavioral; Biological Assay; Brain; Charge; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Computer Analysis; Control Groups; Corpus striatum structure; Data; Disease; Dopamine; Dopamine D1 Receptor; Electrophysiology (science); Ensure; Etiology; FLP recombinase; Family; Frequencies; Functional disorder; Funding; Genes; Genetic; Human; Individual; Injections; Investigation; Ion Channel; Learning; Link; Measures; Mediating; Membrane; Mentorship; Missense Mutation; Monitor; Mus; Mutation; Neurodevelopmental Disorder; Neurons; Nucleus Accumbens; Outcome; Pathway interactions; Pattern; Phenotype; Physiological; Population; Potassium; Potassium Channel; Regulation; Research Personnel; Research Training; Slice; Social Behavior; Social Interaction; Symptoms; System; Techniques; Training; Tyrosine 3-Monooxygenase; Variant; Ventral Striatum; Ventral Tegmental Area; Virus; Voltage-Gated Potassium Channel; Writing; antagonist; autism spectrum disorder; brain circuitry; calcium indicator; dopaminergic neuron; experimental study; falls; gain of function; genetic manipulation; in vivo calcium imaging; in vivo imaging; innovation; insight; mutant; neural; neural circuit; neuronal excitability; neurophysiology; neurotransmitter release; novel; optogenetics; oral communication; preference; proband; sensor; skills; social; voltage

Project Summary Neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD), have complex etiologies and a diversity of phenotypic outcomes. A growing body of evidence implicates deficits in mesostriatal circuitry as contributing to several aspects of behavioral dysregulation associated with these disorders. Underlying these circuit-level dysfunctions, alterations in the brain-wide function of specific ion channels is emerging as a key factor in the etiology of NDDs. A variety of missense mutations in ion channels are found in individuals with NDDs. Many of these mutations occur in genes encoding potassium channels that are among the most diverse regulators of neuronal function, contributing to nearly every aspect of neuronal activity pattern regulation and neurotransmitter release dynamics. The Kv7 family of voltage-gated potassium channels encoded by KCNQ genes are increasingly linked to NDDs including ASD. These channels regulate neuronal excitability and are highly expressed in neurons of the mesostriatal circuitry of the brain. Within this pathway, network activity in the ventral striatum and its inputs from the ventral tegmental area (VTA) which release the neurotransmitter dopamine, regulate numerous behaviors that fall within the symptom domains of several NDDs. Collectively, these data point to Kv7 channels and the mesostriatal system as a potentially critical convergence point that warrants further investigation. It remains unclear how specific ion channels that contribute to mesostriatal circuit regulation impact these network dynamics. Under physiological conditions, Kv7 channels inhibit dopamine neurons, but the Kv7 regulation of excitability is complex. Mutations in all three arginine (R) residues that constitute the gating charges in the S4 transmembrane voltage sensor of KCNQ3 have been identified in NDD and ASD probands. The KCNQ3(R230C) mutant has been the best characterized and results in a gain of function increase in potassium conductance. I hypothesize that KCNQ3(R230C) decreases VTA dopamine neuron activity, resulting in dysregulation of ventral striatum network dynamics and associated dopamine- mediated social behavior. This research training plan will ensure that I master the necessary skill sets in: genetic manipulation of neural circuits, in vivo calcium imaging in freely moving mice, computational analysis, mouse social behavior paradigms, project management, written and oral communication, funding procurement, and mentorship necessary to become an excellent independent researcher.

项目概要 神经发育障碍 (NDD)，例如自闭症谱系障碍 (ASD)，具有复杂的病因，并且 多样化的表型结果。越来越多的证据表明中纹状体回路存在缺陷 导致与这些疾病相关的行为失调的几个方面。底层这些 电路水平功能障碍，特定离子通道的全脑功能的改变正在成为关键 NDD 的病因学因素。在患有以下疾病的个体中发现了离子通道中的多种错义突变 NDD。其中许多突变发生在编码钾通道的基因中，这些基因是最多样化的钾通道之一。 神经元功能的调节剂，对神经元活动模式调节的几乎各个方面都有贡献 神经递质释放动力学。 KCNQ 编码的 Kv7 电压门控钾通道家族 基因与包括 ASD 在内的 NDD 的联系越来越紧密。这些通道调节神经元的兴奋性 在大脑中纹状体回路的神经元中高度表达。在此路径中，网络活动 腹侧纹状体及其来自腹侧被盖区（VTA）的输入，释放神经递质 多巴胺调节多种 NDD 症状范围内的行为。总的来说， 这些数据表明 Kv7 通道和中纹状体系统是一个潜在的关键汇聚点 值得进一步调查。目前尚不清楚特定离子通道如何促进中纹状体 电路调节影响这些网络动态。在生理条件下，Kv7通道抑制 多巴胺神经元，但 Kv7 对兴奋性的调节很复杂。所有三个精氨酸 (R) 残基均发生突变 构成 KCNQ3 的 S4 跨膜电压传感器中的门控电荷已在 NDD 和 ASD 先证者。 KCNQ3（R230C）突变体已得到最好的表征，并导致增益 钾电导功能增加。我假设 KCNQ3(R230C) 降低 VTA 多巴胺 神经元活动，导致腹侧纹状体网络动力学和相关多巴胺失调 介导的社会行为。该研究培训计划将确保我掌握以下方面的必要技能： 神经回路的遗传操作、自由活动小鼠的体内钙成像、计算分析、 小鼠社会行为范式、项目管理、书面和口头交流、资金采购、 和成为一名优秀的独立研究员所必需的指导。