Neurophysiological and pharmacological techniques will be used to investigate cellular mechanisms of epileptogenesis in brain slices of genetically epilepsy-prone rats (GEPRs). Previous work has shown that inferior colliculus (IC) is essential for audiogenic seizures in GEPRs, but that these animals are susceptible to seizures originating in other brain areas. Previous work suggests the hypothesis that epileptogenesis in GEPRs is related to both a reduction in GABAA-mediated inhibitory synaptic transmission, and to an increase in excitatory amino acid (EAA)-mediated excitatory transmission. This hypothesis will be tested in slices of GEPR (GEPR-9 strain) hippocampus (HC) and IC maintained in vitro.
Aim I is to compare EPSPs, IPSPs and the membrane properties of GEPR HC neurons to those of normal rats. Intracellular and extracellular EPSP initial slopes and peak amplitudes will be used as measures of changes in fast excitatory synaptic transmission. Extracellular paired pulse inhibition and intracellular evoked and spontaneous IPSP amplitude and duration will be used as a measures of inhibitory synaptic transmission. An important alternative hypothesis is that epileptogenesis is related to changes in the membrane properties of neurons. Passive membrane properties examined will include neuronal input resistance, resting membrane potential, and charging time constants. Active properties examined will include action potential (AP) height, width, spike frequency accommodation, and a slow afterhyperpolarization which follows repetitive firing of APs. Studies in HC will clarify whether generalized predisposition to seizures in GEPRs is related to changes in amino acid neurotransmission. These studies in HC will be followed by similar studies of IC. The IC is essential for audiogenic seizures, but IC neurons have not yet been well characterized using intracellular recording techniques.
In aim II we will characterize the morphology, membrane properties and synaptic physiology of normal neurons in IC dorsal cortex.
In aim III, these properties will then be compared with those of GEPR IC neurons. These studies will determine whether the special sensitivity of GEPRs to audiogenic seizures may be related to changes in amino acid neurotransmission in IC.
|Li, Y; Evans, M S; Faingold, C L (1998) In vitro electrophysiology of neurons in subnuclei of rat inferior colliculus. Hear Res 121:1-10|
|Evans, M S; Collings, M A; Brewer, G J (1998) Electrophysiology of embryonic, adult and aged rat hippocampal neurons in serum-free culture. J Neurosci Methods 79:37-46|
|Evans, M S; Viola-McCabe, K E (1996) Midazolam inhibits long-term potentiation through modulation of GABAA receptors. Neuropharmacology 35:347-57|
|Verma-Ahuja, S; Evans, M S; Pencek, T L (1995) Evidence for decreased calcium dependent potassium conductance in hippocampal CA3 neurons of genetically epilepsy-prone rats. Epilepsy Res 22:137-44|
|Evans, M S; Viola-McCabe, K E; Caspary, D M et al. (1994) Loss of synaptic inhibition during repetitive stimulation in genetically epilepsy-prone rats (GEPR). Epilepsy Res 18:97-105|
|Li, Y; Evans, M S; Faingold, C L (1994) Inferior colliculus neuronal membrane and synaptic properties in genetically epilepsy-prone rats. Brain Res 660:232-40|