Presynaptic αδ-2 Calcium Channel Subunits Regulate Postsynaptic GABA Receptor Abundance and Axonal Wiring.

Presynaptic αδ 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 αδ isoforms and their role in GABAergic synapses. Using primary neuronal cultures of embryonic mice of both sexes, we here report that presynaptic overexpression of αδ-2 in GABAergic synapses strongly increases clustering of postsynaptic GABARs. Strikingly, presynaptic αδ-2 exerts the same effect in glutamatergic synapses, leading to a mismatched localization of GABARs. This mismatching is caused by an aberrant wiring of glutamatergic presynaptic boutons with GABAergic postsynaptic positions. The trans-synaptic effect of αδ-2 is independent of the prototypical cell-adhesion molecules α-neurexins (α-Nrxns); however, α-Nrxns together with αδ-2 can modulate postsynaptic GABAR abundance. Finally, exclusion of the alternatively spliced exon 23 of αδ-2 is essential for the trans-synaptic mechanism. The novel function of αδ-2 identified here may explain how abnormal αδ subunit expression can cause excitatory-inhibitory imbalance often associated with neuropsychiatric disorders. Voltage-gated calcium channels regulate important neuronal functions such as synaptic transmission. αδ subunits modulate calcium channels and are emerging as regulators of brain connectivity. However, little is known about how individual αδ subunits contribute to synapse specificity. Here, we show that presynaptic expression of a single αδ 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.