Copper Block of Extrasynaptic GABAA Receptors in the Mature Cerebellum and Striatum

Inhibition of GABA(A) receptors by Cu2+ has been appreciated for some time, but differences between synaptic and extrasynaptic GABA(A) receptors have not been explored. We show that Cu2+ potently blocks steady-state GABA currents mediated by extrasynaptic delta subunit-containing GABA(A) receptors (delta-GABA(A)Rs) with an IC50 of 65 nM. This compares with an IC50 of 85 mu M for synaptic gamma subunit-containing GABA(A)Rs (gamma-GABA(A)Rs). To test the significance of this subunit selectivity, we examined the blocking action of Cu2+ on neurons of the mouse cerebellum and striatum, brain regions that are known to express both types of receptor. Cu2+ was shown to significantly reduce tonic inhibition mediated by extrasynaptic delta-GABA(A)Rs with little action on phasic inhibition mediated by conventional synaptic gamma-GABA(A)Rs. We speculate on the implications of these observations for conditions, such as Wilson's disease, that can involve raised Cu2+ levels in the brain.