Tonic GABAA receptor currents in Cerebellar Purkinje cells of wild-type and DMDmdx mice

Abstract

Cerebellar Purkinje cells (PCs) fire spontaneously in the absence of excitatory input and depend heavily on inhibition to modify their firing activity. Previous work in the field has described phasic inhibition arising primarily from molecular layer interneuron-PC (MLI-PC) synapses extensively, however little work explores other sources of inhibition in PCs. Several types of neurons throughout the brain and within the cerebellum receive significant inhibition through tonic currents, a low amplitude current resulting from ambient GABA acting upon extrasynaptic GABAA receptors. Through the use of ex vivo electrophysiology and single cell RNA analysis, we investigated the role of tonic inhibition in PCs. We find that PCs have a significant tonic current mediated by {delta}-subunit containing GABAA receptors, which accounts for roughly half of the total inhibitory current. We also examined PC tonic GABA currents in DMDmdx mice, a mouse model of Duchenne Muscular Dystrophy with [~]50% reduction in phasic inhibitory currents. We find that tonic inhibition is dramatically upregulated in DMDmdx PCs, suggesting a possible compensatory mechanism to account for the loss in phasic inhibition. Furthermore, roughly 80% of the total inhibition is derived from tonic currents in this condition. 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 for PC function. These data reveal an expanded range of inhibitory currents in PC which may be critical to regulating PC activity in both normal and pathophysiological states.