DIFFERENTIAL ACTIVATION OF GABA-A AND GABA-B RECEPTORS BY SPONTANEOUSLY RELEASED TRANSMITTER

1. Whole-cell patch-clamp techniques were used to record from dentate gyrus granule cells in adult rat brain slices when N-methyl-D-aspartate (NMDA) and non-NMDA type glutamate receptors were blocked by D-2-amino-5-phosphonovaleric acid (D-AP5) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), respectively. Spontaneous inhibitory postsynaptic currents (sIPSCs), each presumably due to vesicular release of gamma-aminobutyric acid (GABA), selectively activated GABA(A)-type receptors. None of the individual sIPSCs showed a slow-onset potassium current characteristic of GABA(B) receptor activation. 2. In contrast, stimulation in the molecular layer with a bipolar stimulating electrode or bath application of the convulsant drug 4-aminopyridine (4-AP, 10-30-mu-M) elicited fast GABA(A) IPSCs followed by slower outward currents that were sensitive to the selective GABA(B) antagonist CGP 35348 (0.1-1 mM) and that reversed polarity near the potassium equilibrium potential. 3. CGP 35348 (0.5-1 mM) or the GABA(B) agonist (-)baclofen (1-mu-M) had no significant effect on the frequency or average amplitude of sIPSCs. However, either bath application of (-)baclofen (1-mu-M) or a preceding conditioning stimulus caused large reductions in the amplitude of stimulus-evoked IPSCs, suggesting a strong GABA(B)-mediated presynaptic inhibition of stimulus-evoked GABA release. 4. We conclude that under normal conditions spontaneous transmitter release does not activate GABA(B) receptors in dentate gyrus slices. These findings are consistent with either of two general possibilities. Separate groups of interneurons with different basal firing rates may selectively form GABA(A) and GABA(B) synapses. Alternatively, distinct, activity-dependent modes of transmitter release may be responsible for the differential activation of the two types of GABA receptors. Such distinction in GABAergic synaptic inhibition may have important implications for physiological processes requiring sustained activity or for pathological CNS hyperexcitability.