L-type Ca2+ channel regulation of dendritic arborization

描述(申请人提供)：树突生长是神经回路发育的关键步骤，在癫痫、自闭症和其他神经疾病中受到干扰。电活动通过激活L类电压门控钙通道(LTC)来调节树枝的发育和可塑性。这项建议的目标是了解LTCs如何调控树突生长和树枝形成。为了实现这一目标，我们开发了一种策略，允许我们将突变的LTCs引入神经元，并研究这些外源性通道如何调节树突状突起。初步研究表明，携带G406R突变的LTCs会导致自闭症Timothy综合征(TS)，它们促进树突生长的能力显著受损。我计划对TS突变型LTCs的缺陷进行表征，并研究LTCs的其他生物物理和生化特性如何影响通道调节树突状细胞骨架的能力。这些研究将有助于阐明电活动调节树突生长的机制，也将为自闭症和其他与电压门控钙通道功能障碍相关的神经疾病的分子基础提供重要的见解。

DESCRIPTION (provided by applicant): Dendrite growth is a key step in the development of neuronal circuitry and is perturbed in epilepsy, autism and other neurological diseases. Electrical activity regulates the development and plasticity of dendritic arbors by activating L-type voltage gated Ca2+ channels (LTCs). The goal of this proposal is to understand how LTCs regulate dendritic growth and arborization. To achieve this goal, we have developed a strategy that allows us to introduce mutant LTCs into neurons and to study how these exogenous channels regulate the dendritic arbor. Preliminary studies indicate that LTCs bearing a G406R mutation that causes the autistic disorder Timothy Syndrome (TS), are dramatically impaired in their ability to promote dendrite growth. I plan to characterize the defects of TS mutant LTCs and to investigate how other biophysical and biochemical features of LTCs affect the channel's ability to regulate the dendritic cytoskeleton. These studies will help elucidate the mechanisms by which electrical activity regulates dendritic growth and will also provide critical insight into the molecular underpinnings of autism and other neurological diseases associated with voltage- gated calcium channel dysfunction.