Deletion of Cav2.1(α1A) subunit of Ca2+‐channels impairs synaptic GABA and glutamate release in the mouse cerebellar cortex in cultured slices

Abstract

Deletion of both alleles of the P/Q-type Ca(2+)-channel Ca(v)2.1(alpha(1A)) subunit gene in mouse leads to severe ataxia and early death. Using cerebellar slices obtained from 10 to 15 postnatal days mice and cultured for at least 3 weeks in vitro, we have analysed the synaptic alterations produced by genetically ablating the P/Q-type Ca(2+)-channels, and compared them with the effect of pharmacological inhibition of the P/Q- or N-type channels on wild-type littermate mice. Analysis of spontaneous synaptic currents recorded in Purkinje cells (PCs) indicated that the P/Q-type channels play a prominent role at the inhibitory synapses afferent onto the PCs, with the effect of deleting Ca(v)2.1(alpha(1A)) partially compensated. At the granule cell (GC) to PC synapses, both N- and P/Q-type Ca(2+)-channels were found playing a role in glutamate exocytosis, but with no significant phenotypic compensation of the Ca(v)2.1(alpha(1A)) deletion. We also found that the P/Q- but not N-type Ca(2+)-channel is indispensable at the autaptic contacts between PCs. Tuning of the GC activity implicates both synaptic and sustained extrasynaptic gamma-aminobutyric acid (GABA) release, only the former was greatly impaired in the absence of P/Q-type Ca(2+)-channels. Overall, our data demonstrate that both P/Q- and N-type Ca(2+)-channels play a role in glutamate release, while the P/Q-type is essential in GABA exocytosis in the cerebellum. Contrary to the other regions of the CNS, the effect of deleting the Ca(v)2.1(alpha(1A)) subunit is partially or not compensated at the inhibitory synapses. This may explain why cerebellar ataxia is observed at the mice lacking functional P/Q-type channels.