Mechanisms of GABAB receptor enhancement of extrasynaptic GABAA receptor currents in cerebellar granule cells

Abstract

Abstract Many neurons, including cerebellar granule cells, exhibit a tonic GABA current mediated by extrasynaptic GABA A receptors. This current is a critical regulator of firing and the target of many clinically relevant compounds. Using a combination of patch clamp electrophysiology and photolytic uncaging of RuBi-GABA we show that GABA B receptors are tonically active and enhance extrasynaptic GABA A receptor currents in cerebellar granule cells. This enhancement is not associated with meaningful changes in GABA A receptor potency, mean channel open-time, open probability, or single-channel current. However, there was a significant (~40%) decrease in the number of channels participating in the GABA uncaging current and an increase in receptor desensitization. Furthermore, we find that adenylate cyclase, PKA, CaMKII, and release of Ca 2+ from intracellular stores are necessary for modulation of GABA A receptors. Overall, this work reveals crosstalk between postsynaptic GABA A and GABA B receptors and identifies the signaling pathways and mechanisms involved.