The proposed Program uses approaches within the disciplines of neuroanatomy, neuropharmacology, and neurophysiology to study a) electrophysiological abnormalities in injured neurons and those of chronic epileptiform foci; b) the physiology of GABA-ergic neurons in cortex and thalamus; c) actions of neurotransmitters including ACh, GABA, norepinephrine, and serotonin; d) normal organization and physiology of cortical neurons and mechanisms for initiation and propagation of epileptiform discharges in cortex; e) influences of ascending cholinergic and noradrenergic systems on cortical neuronal activities and epileptiform spike-wave activities in a simple vertebrate nervous system; f) the role of serotonin subtypes and modulation of cortical excitability; and g) mechanisms of glutamate neurotoxicity on cortical neurons. The specific projects are: I. Regulation of neuronal excitability and epileptogenesis; II. Functional organization of local cortical circuits; III. Serotonin receptor subtypes and cortical excitability; IV. Subcortical influences on cortical excitability; and V. Glutamate neurotoxicity. The techniques employed include intracellular recordings; application of neurotransmitters and other agents; patch clamp recordings of whole cell currents; field potential analysis; use of cortical slice, cultured and acutely dissociated neocortical neurons and turtle nervous system in vitro; intracellular and retrograde neuronal labeling; immunocytochemistry; radioligand binding and autoradiography. The long-term goals of the Program are to obtain information which will provide a better understanding of the pathogenesis of epilepsy and insights which will lead to the development of rational new approaches to the prevention and treatment of this disorder. The studies outlined will also contribute to our understanding of normal regulation of cerebral excitability through effects of functional connections, specific transmitter systems, and intrinsic neuronal properties.
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