| First Author | Geisler S | Year | 2019 |
| Journal | J Neurosci | Volume | 39 |
| Issue | 14 | Pages | 2581-2605 |
| PubMed ID | 30683685 | Mgi Jnum | J:274323 |
| Mgi Id | MGI:6287329 | Doi | 10.1523/JNEUROSCI.2234-18.2019 |
| Citation | Geisler S, et al. (2019) Presynaptic alpha2delta-2 Calcium Channel Subunits Regulate Postsynaptic GABAA Receptor Abundance and Axonal Wiring. J Neurosci 39(14):2581-2605 |
| abstractText | Presynaptic alpha2delta 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 alpha2delta isoforms and their role in GABAergic synapses. Using primary neuronal cultures of embryonic mice of both sexes, we here report that presynaptic overexpression of alpha2delta-2 in GABAergic synapses strongly increases clustering of postsynaptic GABAARs. Strikingly, presynaptic alpha2delta-2 exerts the same effect in glutamatergic synapses, leading to a mismatched localization of GABAARs. This mismatching is caused by an aberrant wiring of glutamatergic presynaptic boutons with GABAergic postsynaptic positions. The trans-synaptic effect of alpha2delta-2 is independent of the prototypical cell-adhesion molecules alpha-neurexins (alpha-Nrxns); however, alpha-Nrxns together with alpha2delta-2 can modulate postsynaptic GABAAR abundance. Finally, exclusion of the alternatively spliced exon 23 of alpha2delta-2 is essential for the trans-synaptic mechanism. The novel function of alpha2delta-2 identified here may explain how abnormal alpha2delta 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. alpha2delta subunits modulate calcium channels and are emerging as regulators of brain connectivity. However, little is known about how individual alpha2delta subunits contribute to synapse specificity. Here, we show that presynaptic expression of a single alpha2delta 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. |
