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

Presynaptic α₂δ 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 α₂δ isoforms and their role in GABAergic synapses. Using primary neuronal cultures of embryonic mice of both sexes, we here report that presynaptic overexpression of α₂δ-2 in GABAergic synapses strongly increases clustering of postsynaptic GABA_ARs. Strikingly, presynaptic α₂δ-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 of α₂δ-2 is independent of the prototypical cell-adhesion molecules α-neurexins (α-Nrxns); however, α-Nrxns together with α₂δ-2 can modulate postsynaptic GABA_AR abundance. Finally, exclusion of the alternatively spliced exon 23 of α₂δ-2 is essential for the trans-synaptic mechanism. The novel function of α₂δ-2 identified here may explain how abnormal α₂δ subunit expression can cause excitatory-inhibitory imbalance often associated with neuropsychiatric disorders.SIGNIFICANCE STATEMENT Voltage-gated calcium channels regulate important neuronal functions such as synaptic transmission. α₂δ subunits modulate calcium channels and are emerging as regulators of brain connectivity. However, little is known about how individual α₂δ subunits contribute to synapse specificity. Here, we show that presynaptic expression of a single α₂δ variant can modulate synaptic connectivity and the localization of inhibitory postsynaptic receptors. Our findings provide basic insights into the development of specific synaptic connections between nerve cells and contribute to our understanding of normal nerve cell functions. Furthermore, the identified mechanism may explain how an altered expression of calcium channel subunits can result in aberrant neuronal wiring often associated with neuropsychiatric disorders such as autism or schizophrenia.