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Altered Astrocyte-Neuron Interactions and Epileptogenesis in Tuberous Sclerosis Complex Disorder

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Annual rept. 1 Jun 2012-31 May 2013

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While the molecular basis of TSC is well established, far less is known about the pathogenetic mechanisms of epileptogensis in TSC, shich is found in the vast majority of patients. We introduce the novel concept that this follows from a disruption of normal synaptic pruning that is due to TSC mutation in astrocytes, the major non-neuronal cell type of the brain. Previous studies mostly focused on focal epileptogenisis in cortical tubers. In this study, we propose that nontuber cortex may present an abnormally excitable neuronal network that could underlie seizure generation. We will concentrate on a non-neuronal mechanism may exist in regulating synaptic function and thus epileptogenisis in TSC. To explore this aim, we will use a wide variety of experimental approaches, including electrophysiological patch-clamping in culture cells and slice preparations to in vivo video-EEG monitoring, histological conventional and fluorescent assays, molecular biological Western blotting, biotinylation, and modern cellular imaging confocal and two-photon microscopy of tissue preparations techniques. We will measure biomarkers for astrocyte and neuronal functions and provide an index of glial transmission in the cortex of TSC deficient mouse models and peri-tuber or non-tuber tissue from TSC human brain. We will determine whether astrocyte dysfunction will lead to a failure in pruning excessive excitatory synapses during development, which underlies epilepsy in young TSC patients.

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  • Medicine and Medical Research

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