Epilepsy is a neurological disorder afflicting nearly 3 million patients in this country alone. It is thought to arise through reorganization of neural circuitry often following injury. However those aspects of reorganization that are adaptive, and will prevent the eventual development of epilepsy, vs those that are maladaptive and will lead to epileptogenesis, remain unclear. This program brings together the expertise of 3 investigators into a collaborative team that will address different aspects of circuit reorganization relevant to epileptogenesis. In project 1, David Prince, will determine whether down regulation of ATPase in inhibitory axons and terminals of injured, undercut cortex leads to defects in synaptic inhibition and whether basket cells, a major class of inhibitory neurons, become functionally deafferented from their postsynaptic targets. In project 2, John Huguenard will use the freeze lesion model of focal cortical dysplasia to test whether reduced GluR2 expression in synapses of neocortical pyramidal neurons renders them susceptible to aberrant and potentially epileptogenic modulation by PKC and BDNF. In addition, using laser scanning photostimulation he will determine whether altered GluR2 expression and rewiring contribute to generation of neocortical epileptic discharge in this model. In project 3, Paul Buckmaster will use pilocarpine model of temporal lobe epilepsy and array electrodes to identify regions in the limbic system with the most predictive power for seizures, and then develop algorithms for seizure detection and prediction. He will also test whether altered connectivity between granule cells and interneurons explains a lack interneuronal recruitment in the preictal period. A core component will provide key administrative, histological and technical support for all projects. Together, the results of these studies will provide information regarding common vs distinct mechanisms of epileptogenesis in models of focal cortical, temporal lobe and post-traumatic epilepsies.
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