Adenosine A1 Receptor Suppresses Tonic GABAA Receptor Currents in Hippocampal Pyramidal Cells and in a Defined Subpopulation of Interneurons

Adenosine is an endogenous neuromodulator that decreases excitability of hippocampal circuits activating membrane-bound metabotropic A(1) receptor (A(1)R). The presynaptic inhibitory action of adenosine A(1)R in glutamatergic synapses is well documented, but its influence on inhibitory GABAergic transmission is poorly known. We report that GABA(A) receptor (GABA(A)R)-mediated tonic, but not phasic, transmission is suppressed by A(1)R in hippocampal neurons. Adenosine A(1)R activation strongly inhibits GABA(A)R agonist (muscimol)-evoked currents in Cornu Ammonis 1 (CA1) pyramidal neurons and in a specific subpopulation of interneurons expressing axonal cannabinoid receptor type 1. In addition, A(1)R suppresses tonic GABA(A)R currents measured in the presence of elevated ambient GABA as well as in na < ve slices. The inhibition of GABAergic currents involves both protein kinase A (PKA) and protein kinase C (PKC) signaling pathways and decreases GABA(A)R delta-subunit expression. On the contrary, no A(1)R-mediated modulation was detected in phasic inhibitory postsynaptic currents evoked either by afferent electrical stimulation or by spontaneous quantal release. The results show that A(1)R modulates extrasynaptic rather than synaptic GABA(A)R-mediated signaling, and that this modulation selectively occurs in hippocampal pyramidal neurons and in a specific subpopulation of inhibitory interneurons. We conclude that modulation of tonic GABA(A)R signaling by adenosine A(1)R in specific neuron types may regulate neuronal gain and excitability in the hippocampus.