Defense Date

2008

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Anatomy & Neurobiology

First Advisor

Kimberle Jacobs

Abstract

The propensity for seizures in patients with epilepsy is due to underlying cortical hyperexcitability, the mechanisms of which are poorly understood. Particularly difficult to treat are patients with developmental malformations of cortex. Using the freeze-lesion rat model of one such malformation, polymicrogyria, we identified, in lesioned cortex, alterations in specific interneuron subpopulations that may promote hyperexcitability. Previous studies demonstrate increased excitatory input to the paramicrogyral region. An increase in the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) recorded from pyramidal cells has also been shown. We report an increase in sEPSCs recorded from one subtype of interneuron, the low threshold-spiking interneuron (LTS), while sEPSCs in the fast-spiking (FS) interneuron remain unchanged. Distributed equally to pyramidal cells and interneurons, extra excitatory afferents should simply increase overall activity level but maintain the balance of excitation and inhibition. Selective changes in one or more interneuron subpopulations could allow inhibition to appear unchanged, while permitting problematic alterations in inhibitory circuitry. In what appears to be a morphological division of labor, interneurons with intralaminar orientations are typically characterized as FS, while intracolumnar orientations are associated with LTS cells. These cells are clearly distinguished by a combination of visual identification and electrophysiological and intrinsic properties. We report that these characteristics are unchanged in lesioned cortex, indicating that the malformation is not responsible for intrinsic alteration of the cell types. However, some firing properties demonstrate slight differences that may, in cooperation with the altered level of input, amplify the pro-epileptogenic changes in circuitry. Finally, we also report that there is anomalous expression of metabotropic glutamate receptors (mGluR) in malformed cortex. Our data show that the expression of mGluR5, normally causing no functional response in control cortex, contributes to the activation of interneurons in paramicrogyral (PMG) cortex. These findings provide new insight to the mechanisms of cortical hyperexcitability and identify a possible target for future pharmacological intervention.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

December 2008

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