Tonic GABA_A receptor currents in Cerebellar Purkinje cells of wild-type and DMD^mdx mice

Cerebellar Purkinje cells (PCs) fire spontaneously and depend heavily on inhibition to modify their activity. While phasic inhibition is well-described in PCs, the presence and mechanisms of tonic inhibitory currents, low amplitude currents resulting from ambient GABA acting upon extrasynaptic GABA_A receptors, are still unclear. Using ex vivo electrophysiology and single cell RNA analysis in C57BL/6J mice, we find that PCs have a significant tonic current mediated by δ-subunit containing GABA_A receptors, which accounts for roughly half of the total inhibition. We also examined PC tonic GABA currents in DMD^mdx mice, a mouse model of Duchenne Muscular Dystrophy with ~ 50% reduction in phasic inhibitory currents. We find that tonic inhibition is dramatically upregulated in DMD^mdx PCs, suggesting a possible compensatory mechanism in response to loss of phasic inhibition. Furthermore, roughly 80% of the total inhibition is derived from tonic currents in DMD^mdx PCs. These data suggest that under physiological conditions, PCs are subject to both tonic and phasic inhibition, and that adjustments in the balance of inhibition may be a physiological mechanism regulating PC function. These data reveal an expanded range of inhibitory currents in PCs which may be critical to regulating PC activity in both normal and pathophysiological states.