Presynaptic α2δ-2 Calcium Channel Subunits Regulate Postsynaptic GABAA Receptor Abundance and Axonal Wiring

Presynaptic alpha(2)delta subunits of voltage-gated calcium channels regulate channel abundance and are involved in glutamatergic synapse formation. However, little is known about the specific functions of the individual alpha(2)delta isoforms and their role in GABAergic synapses. Using primary neuronal cultures of embryonic mice of both sexes, we here report that presynaptic overexpression of alpha(2)delta-2 in GABAergic synapses strongly increases clustering of postsynaptic GABA(A)Rs. Strikingly, presynaptic alpha(2)delta-2 exerts the same effect in glutamatergic synapses, leading to a mismatched localization of GABA(A)Rs. This mismatching is caused by an aberrant wiring of glutamatergic presynaptic boutons with GABAergic postsynaptic positions. The trans-synaptic effect of alpha(2)delta-2 is independent of the prototypical cell-adhesion molecules alpha-neurexins (alpha-Nrxns); however, alpha-Nrxns together with alpha(2)delta-2 can modulate postsynaptic GABA(A)R abundance. Finally, exclusion of the alternatively spliced exon 23 of alpha(2)delta-2 is essential for the trans-synaptic mechanism. The novel function of alpha(2)delta-2 identified here may explain how abnormal alpha(2)delta subunit expression can cause excitatory-inhibitory imbalance often associated with neuropsychiatric disorders.