Neuronal migration disorders have been recognized from neuropathological studies for over 100 years and were traditionally thought to be associated with severe neurological impairment and to cause death at an early age. However, the advent of modern high resolution magnetic resonance imaging has resulted in the detection of NMDs in living patients. These brain lesion appear to underlie some forms of human epilepsy and are associated with mental retardation. Freezing lesions of the developing rat brain reproduce many of the anatomical findings in human cortex. Freeze-induced microgyria will be used as a model system for studying the consequences of cortical malformations . The principal aim of the proposed research is to determine the mechanisms underlying epileptiform discharges originating from experimentally induced microgyria in rat neocortex. Proposed studies will use quantitative biophysical methods, including whole-cell patch clamping of visually identified neurons and optical imaging, to identify the cellular abnormalities which underlie epileptiform discharges in focal gyral anomalies. It is planned: 1) to investigate if there is a loss of GABA-mediated inhibition in the microgyrus and adjacent region; 2) to determine if alterations in excitatory amino acid mediated excitatory synaptic transmission are present in microgyri; 3) to ascertain if metabotropic glutamate receptors are altered in microgyri, and 4) to characterize the site of origin and pattern of spread of epileptiform discharges in microgyri using voltage-sensitive dyes and optical imaging techniques. The proposed studies will increase our understanding of basic mechanisms of epileptogenesis in cortical malformations.
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