Tonic GABAreceptor currents in Cerebellar Purkinje cells of wild-type and DMDmice.

Abstract

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 GABAreceptors, 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 GABAreceptors, which accounts for roughly half of the total inhibition. We also examined PC tonic GABA currents in DMDmice, a mouse model of Duchenne Muscular Dystrophy with ~ 50% reduction in phasic inhibitory currents. We find that tonic inhibition is dramatically upregulated in DMDPCs, 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 DMDPCs. 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.