Evidence for a functional role of GABA receptors in the rat mature hippocampus

Both gamma-aminobutyric acid (GABA)(C) receptor subunit mRNA and protein are expressed in the stratum pyramidale in the CA1 area of the adult rat hippocampus, but so far no conclusive evidence about functional hippocampal GABA(C) receptors has been presented. Here, the contribution of GABA(C) receptors to stimulus-evoked postsynaptic potentials was studied in the hippocampal CA1 area with extracellular and intracellular recordings at the age range of 21-47 postnatal days. Activation of GABA(C) receptors with the specific agonist cis-4-aminocrotonic acid (CACA) suppressed postsynaptic excitability and increased the membrane conductance. The GABA(C) receptor antagonist 1,2,5,6-tetrahydropyridine-4-ylmethylphosphinic acid (TPMPA), but not the GABA(A) receptor antagonist bicuculline, inhibited the effects of CACA. GABA-mediated long-lasting depolarizing responses evoked by high-frequency stimulation of local inhibitory interneurons in the CA1 area in the presence of ionotropic glutamate receptor and GABA(B) receptor blockers were prolonged by TPMPA, indicating that GABA(C) receptors are activated under these conditions. For weaker stimulation, the effect of TPMPA was enhanced after GABA uptake was inhibited. Our data demonstrate that GABA(C) receptors can be activated by endogenous synaptic transmitter release following strong stimulation or under conditions of reduced GABA uptake. The lack of GABA(C) receptor activation by less intensive stimulation under control conditions suggests that these receptors are extrasynaptic and activated via spillover of synaptically released GABA.