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 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.