Abstracts

The inferior colliculus (IC) neurons are thought to be critical in the initiation of audiogenic reflex seizures in the genetically epilepsy-prone rat (GEPR). We previously reported that high voltage-activated (HVA) Ca²⁺ channel current density was markedly enhanced in IC neurons of seizure-naive GEPR-3. Ca²⁺ currents are known to activate K⁺ currents that initiate the repolarization of action potential and hyperpolarize the membrane. Such Ca²⁺-activated K⁺ currents may represent intrinsic inhibitory mechanisms that would restore the resting state and maintain normal physiological excitability. Whether change in Ca²⁺-activated K⁺ current density parallel the upregulation of HVA Ca²⁺ channel current density reported in IC neurons of GEPR-3 is as yet unknown. Here we report on the expression of Ca²⁺-activated K⁺ currents in IC neurons and their modification in seizure-naive GEPR-3., Acutely dissociated neurons of the IC central nucleus were obtained from male seizure-naive GEPR-3s (12-15 week-old) and age-matched control Sprague-Dawley rats. The currents through K⁺ channels were recorded using the whole cell configuration of the patch clamp techniques. Ca²⁺-activated K⁺ currents were recorded in the presence of 2 mM extracellular Ca²⁺, while dialyzing the neurons with 100 nM free Ca²⁺ (buffered with 0.5 mM EGTA and Ca²⁺). Currents were normalized relative to the membrane capacitance as an estimate of current density., Quantification of the current evoked at +20 mV (holding potential -50 mV) showed that the mean peak current density of total Ca²⁺-activated K⁺ current was decreased by [sim]40% in IC neurons of seizure-naive GEPR-3 (n = 3 cells, 3 rats) that expressed elevated HVA Ca²⁺ channel current density, as compared to controls (n = 8 cells, 3 rats) Quantification of the voltage dependence of total Ca²⁺-activated K⁺ current shows a downregulation of the current density at all voltages tested, on the average, by 60 [plusmn] 6% in IC neurons of the GEPR-3 (n = 3 cells, 3 rats), as compared to controls (n = 8 cells, 3 rats). We are currently examining the contribution of various fraction of the current carried by large and small conductance subtype of Ca²⁺-activated K⁺ channels., The data suggest that Ca²⁺-activated K⁺ current density is downregulated and parallel the enhancement of HVA Ca²⁺ channel current density in IC neurons of seizure-na ve GEPR-3. The upregulation of HVA Ca²⁺ channel current density and downregulation of Ca²⁺-activated K⁺ current density may provide a cohesive mechanism for neuronal hyperexcitability that lead to seizures and mechanistic insights into therapeutic strategies for generalized epilepsy., (Supported by NIH grants NS05497 (P.N.), AA11628 (C.L.F) and HL16152 (M.M.).)