Copper block of extrasynaptic GABAA receptors in the mature cerebellum and striatum.

Inhibition of GABAA receptors by Cu(2+) has been appreciated for some time, but differences between synaptic and extrasynaptic GABAA receptors have not been explored. We show that Cu(2+) potently blocks steady-state GABA currents mediated by extrasynaptic δ subunit-containing GABAA receptors (δ-GABAARs) with an IC50 of 65 nM. This compares with an IC50 of 85 μM for synaptic γ subunit-containing GABAARs (γ-GABAARs). To test the significance of this subunit selectivity, we examined the blocking action of Cu(2+) on neurons of the mouse cerebellum and striatum, brain regions that are known to express both types of receptor. Cu(2+) was shown to significantly reduce tonic inhibition mediated by extrasynaptic δ-GABAARs with little action on phasic inhibition mediated by conventional synaptic γ-GABAARs. We speculate on the implications of these observations for conditions, such as Wilson's disease, that can involve raised Cu(2+) levels in the brain.