Mechanisms of GABA_B receptor enhancement of extrasynaptic GABA_A receptor currents in cerebellar granule cells

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 Ca²⁺ 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.