ISCHEMIA-RELATED ALTERATION OF GABA(A)-OPERATED CHLORIDE CHANNEL PROPERTIES IN GERBIL HIPPOCAMPUS AND CEREBRAL-CORTEX

The properties of GABA-gated chloride (Cl-) channels in ischemia-reper fusion injury were studied by determination of the binding and dissoci ation kinetics of a specific Cl- channel ligand, tert-butylbicyclophos phoro [(35) S] thionate (TBPS) and by determination of Cl-36(-) uptake in the presence of the GABA(A) receptor agonist, muscimol. Four days after ischemia a small but insignificant decrease of [S-35]TBPS bindin g to synaptic plasma membranes (SPM) was observed in the hippocampus a nd cerebral cortex as compared to control. The effect of ischemia was larger and statistically significant after the first and second month of reperfusion, constituting 20% inhibition of [S-35]TBPS binding to S PM of sham-operated gerbils. On the other hand, the half-life of fast phase [S-35]TBPS dissociation four days after ischemia was markedly di minished by about 40%-50% as compared to its control value and persist ed during the first and second month of reperfusion in the hippocampal SPM. A similar but less potent reduction of the half-life of the fast phase of [S-35]TBPS dissociation (about 30% versus control) appeared one and two months after ischemia in cerebral cortex SPM. One month af ter ischemia muscimol-stimulated Cl-36(-) uptake into cerebral cortex synaptoneurosomes was lowered as compared with control uptake, but rem ained statistically insignificant in the whole range of muscimol conce ntrations tested. Our results indicated that ischemia-reperfusion inju ry significantly decreases opening time of GABA(A) receptor-gated Cl- channels in the hippocampus and cerebral cortex, which may lower the h yperpolarization ability of this receptor complex leading to an imbala nce between excitatory and inhibitory neurotransmitter pathways in the se brain areas, and in consequence to neuronal dysfunction or degenera tion.