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

Inhibition of GABAA receptors by Cu2+ has been appreciated for some time, but differences between synaptic and extrasynaptic GABAA receptors have not been explored. We show that Cu2+ 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 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 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 Cu2+ levels in the brain.