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

Presynaptic α ₂δ 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 α ₂δ isoforms and their role in GABAergic synapses. Using primary neuronal cultures of embryonic mice of both sexes, we here report that presynaptic overexpression ofα ₂δ-2 in GABAergic synapses strongly increases clustering of postsynaptic GABA _ARs. Strikingly, presynaptic α ₂δ-2 exerts the same effect in glutamatergic synapses, leading to a mismatched localization of GABA _ARs. This mismatching is caused by an aberrant wiring of glutamatergic presynaptic boutons with GABAergic postsynaptic positions. The trans-synaptic effect ofα ₂δ-2 is independent of the prototypical cell-adhesion molecules α-neurexins (α-Nrxns); however, α-Nrxns together with α ₂δ-2 can modulate postsynaptic GABA _AR abundance. Finally, exclusion of the alternatively spliced exon 23 of α ₂δ-2 is essential for the trans-synaptic mechanism. The novel function of α ₂δ-2 identified here may explain how abnormal α ₂δ subunit expression can cause excitatory-inhibitory imbalance often associated with neuropsychiatric disorders.