α2δ-2 mediates coupling of presynaptic calcium entry to vesicle release in hippocampal parvalbumin-expressing interneurons
TL;DR
Using electrophysiological recordings from genetically modified mice, α2δ-2 functionally couples calcium entry to vesicle release from parvalbumin-expressing cells, which provides a potential explanation for the seizure phenotype of α2δ-2 mutant mice and illuminates the broader roles of α2δ proteins in neuronal function.
Abstract
The α2δ family of auxiliary voltage-gated calcium channel (VGCC) subunits have critical but incompletely understood roles in brain function. Parvalbumin-positive (PV+) interneurons in the hippocampus highly express the α2δ-2 isoform, and mice lacking α2δ-2 exhibit spontaneous seizures. Thus, we examined PV+ neuron-mediated synaptic inhibition in acutely prepared brain slices from α2δ-2 knockout (KO) mice. In the inner molecular layer of the dentate gyrus, α2δ-2 KO mice demonstrated an increase in the excitation/inhibition ratio of synaptic inputs onto granule cells. We then used optogenetics to activate PV+ interneurons, which produced dramatically smaller inhibitory synaptic currents in granule cells from α2δ-2 KO mice. There was a reduction in PV+ inputs onto granule cells as determined by immunostaining. Functionally, these inputs had a lower probability of GABA release and a decreased readily releasable pool of vesicles compared to littermate controls. VGCC coupling to presynaptic vesicle release was also reduced in dentate gyrus PV+ cells in α2δ-2 KO mice, based on manipulations of intracellular and extracellular calcium. Together, our data indicate that α2δ-2 plays a critical role in PV+ interneuron-mediated synaptic inhibition, which may contribute to seizures in α2δ-2 mutant mice. Significance Statement A family of auxiliary VGCC subunits, the α2δs, plays a variety of important roles in brain function, although its underlying mechanisms are poorly understood. Here, we use mouse models to determine that the α2δ-2 isoform plays a critical role in the presynaptic function of parvalbumin-expressing interneurons in the hippocampal dentate gyrus. Using electrophysiological recordings from genetically modified mice, we find that α2δ-2 functionally couples calcium entry to vesicle release from parvalbumin-expressing cells. This finding not only provides a potential explanation for the seizure phenotype of α2δ-2 mutant mice but also illuminates the broader roles of α2δ proteins in neuronal function.