Adenosine-mediated inhibition of striatal GABAergic synaptic transmission during in vitro ischaemia

Several reports have shown that energy deprivation, as a result of hypoxia, hypoglycaemia or ischaemia, depresses excitatory synaptic transmission in virtually all brain areas. How this pathological condition affects inhibito ry synaptic transmission is still unclear. In the present in vitro study, w e coupled whole-cell patch clamp recordings from striatal neurones with foc al stimulation of GABAergic nerve terminals in order to characterize the el ectrophysiological effects of combined oxygen and glucose deprivation (in v itro ischaemia) on inhibitory postsynaptic currents (IPSCs) in this brain a rea. We found that brief periods (2-5 min) of in vitro ischaemia invariably caused a marked depression of IPSC amplitude. This inhibitory effect was f ully reversible on removal of the ischaemic challenge. It was coupled with an increased paired-pulse facilitation, suggesting the involvement of presy naptic mechanisms. Accordingly, the ischaemic inhibition of striatal GABAer gic IPSCs was not caused by a shift in the reversal potential of GABA(A)-re ceptor mediated synaptic currents, and was independ- ent of postsynaptic AT P concentrations. Endogenous adenosine, acting on A1 receptors, appeared re sponsible for this presynaptic action as the ischaemic depression of IPSCs was prevented by CPT [8-(4-chlorophenylthio) adenosine] and DPCPX, two aden osine A1 receptor antagonists, and mimicked by the application of adenosine in the bathing solution. Conversely, ATP-sensitive potassium channels were not involved in the inhibition of IPSCs by ischaemia, as demonstrated by t he fact that tolbutamide and glipizide, two blockers of these channels, wer e ineffective in preventing this electrophysiological effect. The early dep ression of GABA-mediated synaptic transmission might play a role in the dev elopment of irreversible neuronal injury in the course of brain ischaemia.