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

项目摘要 神经发育障碍(NDDS)，如自闭症谱系障碍(ASD)，有复杂的病因和 表型结果的多样性。越来越多的证据表明中纹状体环路的缺陷 导致与这些障碍相关的行为失调的几个方面。在这些基础上 电路水平的功能障碍，脑内特定离子通道功能的改变正在成为一个关键 NDDS的病因学因素。离子通道中的各种错义突变在患有 NDDS。其中许多突变发生在编码钾通道的基因中，钾通道是最多样化的 神经元功能的调节器，对神经元活动模式调节的几乎每一个方面都有贡献 神经递质释放动力学。KCNQ编码的电压门控性钾通道KV7家族 基因越来越多地与包括ASD在内的NDDS联系在一起。这些通道调节神经元的兴奋性，并 在大脑中纹状体环路的神经元中高表达。在这条路径中，网络活动在 腹侧纹状体及其来自腹侧被盖区(VTA)的输入释放神经递质 多巴胺调节属于几种NDD症状范围内的许多行为。总而言之， 这些数据表明，KV7通道和中纹状体系统是一个潜在的关键会聚点， 需要进一步调查。目前尚不清楚特定的离子通道对中纹状体有多大作用 电路调节会影响这些网络动态。在生理条件下，KV7通道抑制 多巴胺神经元，但KV7对兴奋性的调节是复杂的。所有三个精氨酸(R)残基的突变 构成KCNQ3的S4跨膜电压传感器的门控电荷已在 NDD和ASD先证者。KCNQ3(R230C)突变体是特征最好的，其结果是获得了 功能钾电导增加。我推测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的多巴胺- 居间社交行为。这项研究培训计划将确保我在以下方面掌握必要的技能： 神经回路的遗传操作，自由移动的小鼠体内钙成像，计算分析， 鼠标社会行为范例、项目管理、书面和口头交流、资金采购、 以及成为一名优秀的独立研究人员所必需的导师。

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.