Role of TSC1 in the Formation and Maintenance of Excitatory Synapses

摘要

Tuberous Sclerosis (TSC) is an autosomal dominant genetic disorder characterized by benign tumors of many organs. The majority of TSC patients are identified as children and most have neurological symptoms including mental retardation and epilepsy. Although it is known that TSC results from mutations in either the TSC1 or TSC2 genes, the pathogenesis of the neurological disorder is unclear. One possibility, inspired by gross pathological findings, is that the presence of benign growths in the brain leads to disorganized and compressed brain tissue and perturbed neural circuits. However, it is equally possible that loss of TSC1 or TSC2 disrupts neuronal function in a cell- autonomous manner. Our hypothesis is that TSC1 is necessary in mature, differentiated neurons for the establishment of proper neuronal morphology and synaptic function. This hypothesis is being testing by examining cell- autonomous defects in TSC1 null neurons located within otherwise normal brain tissue. The approaches used to examine the perturbed cells are immunostaining of activated proteins in the TSC signaling cascade, optical microscopy of neuronal structure, and electrophysiological analysis of electrical properties.