Many neurons, including cerebellar granule cells, exhibit a tonic GABA current mediated by extrasynaptic GABAA 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 GABAB receptors are tonically active and enhance extrasynaptic GABAA receptor currents in cerebellar granule cells. This enhancement is not associated with meaningful changes in GABAA 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 GABAA receptors. Overall, this work reveals crosstalk between postsynaptic GABAA and GABAB receptors and identifies the signaling pathways and mechanisms involved.
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