Novel Na _V 1.6 ‐Mitochondrial Complexes in Retinal Astrocyte Pockets Sequester <

ABSTRACT

Voltage‐gated sodium channels are best known for their capacity to generate and propagate electrical currents in neurons and muscle. Their expression in glial cells may also be of great importance given these cells' involvement in various disease processes. Here we identify a previously unrecognized voltage‐gated sodium channel Na _V 1.6‐enriched microdomain in mouse retinal astrocytes. Using super‐resolution confocal microscopy, electrophysiology, and transcriptomic analyses, we show that Na _V 1.6 forms high‐density clusters within intracellular compartments devoid of the calcium‐binding protein, S100β, typically understood to distribute throughout the entire astrocyte. These Na _V 1.6 pockets are polarized, clustering only on the bilayer facing retinal ganglion cell neurons, and are packed with unusually large, anaplerotic, and relatively depolarized mitochondria that closely appose Na _V 1.6 puncta. These metabolic compartments also accumulate high levels of GABA. Together, our findings reveal a specialized Na _V 1.6‐mitochondrial complex in retinal astrocytes that expands the functional repertoire of voltage‐gated sodium channels beyond direct neuronal electrical excitability.