L-type Ca2+ channel regulation of dendritic arborization

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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.