Epilepsy is a devastating neurological disorder that affects 6.25/1,000 people in the U.S. About 30 to 40% of people with epilepsy cannot be adequately treated with medications (intractable epilepsy). Congenital abnormalities of cortical development (previously called disorders of neuronal migration) are a common substrate for intractable epilepsy in children and adults. Cortical dyplasia is the most common example of this type of disorder and it involves abnormalities of cytoarchitecture and neuronal morphology in the neocortex. The current project utilizes the in utero-irradiated rat as an animal model of cortical dysplasia and epilepsy. Findings from the initial funding period showed a selective loss of inhibitory interneurons in dysplastic cortex and a corresponding reduction in inhibitory postsynaptic currents in pyramidal neurons in dysplastic and heterotopic cortex in irradiated rats. The current proposal will expand on these studies of impaired inhibition by performing whole cell recordings directly from an important sub-type of interneuron (parvalbumin containing, fast-spiking interneurons = PA/FS) in dysplastic and control cortex.
In Specific Aim 1, excitatory and inhibitory currents in PA/FS interneurons will be analyzed as well as short term plasticity of these currents.
Specific Aim 2 will record from synaptically connected pairs of PA/FS:pyramidal neurons to obtain unitary IPSCs. These currents will be analyzed to look for differences in release probability, number of synapses, and quantal size between interneurons and their neighboring pyramidal neurons. Morphological analyses will also be performed to determine if the surviving interneurons in dysplastic cortex make any compensatory increases in connectivity with their neighbors.
In Specific Aim 3, we will investigate why the interneurons are lacking in dysplastic cortex. We will double-label late-generated interneurons for BrdU and GABA after the irradiation injury and determine the number of these cells in the neocortex and subcortical white matter at age 2 weeks. This will tell us if the interneurons are killed by the irradiation or if they are simply arrested in their migratory pathway in the subcortical white matter. These experiments will advance our understanding of cortical dysplasia and epilepsy and give greater insight the mechanisms that produce long-term impairment of inhibition after an isolated in utero injury.
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