GABA(B) AUTORECEPTORS MEDIATE ACTIVITY-DEPENDENT DISINHIBITION AND ENHANCE SIGNAL TRANSMISSION IN THE DENTATE GYRUS

1. Activity-dependent depression (fading) of polysynaptic inhibition and the effects of this disinhibition on signal transmission were studied in the dentate gyrus of the rat hippocampal slice with the use of intracellular and extracellular recordings. 2. Polysynaptic inhibitory postsynaptic potentials/currents (IPSP/Cs) were evoked in dentate granule cells by stimulation of mossy fibers in stratum lucidum of area CA3b/c. These mossy fiber-evoked IPSP/Cs consisted of an early GABA(A) receptor-mediated component (IPSP/C(A)) and a late GABA(B) receptor-mediated component (IPSP/C(B)). 3. When paired stimuli were delivered 200 ms apart under voltage clamp, the amplitude of the IPSC(A) and IPSC(B) evoked by the second stimulus was reduced by 37.0 +/- 4.0 and 61.6 +/- 7.8% (mean +/- SE), respectively. Paired-pulse depression of both IPSC(A) and IPSC(B) was greatest at interstimulus intervals of 100-400 ms with a maximal effect when stimuli were delivered 200 ms apart. 4. (+/-)Baclofen, a GABA(B) receptor agonist, suppressed both components of the mossy fiber-evoked IPSP in a concentration-dependent fashion. At a concentration that only partially suppressed the initial IPSP, baclofen occluded paired-pulse depression of IPSP(A). In addition, paired-pulse depression of IPSP(A) was blocked in a concentration-dependent fashion by 2-hydroxy-saclofen (10-400 muM), a GABA(B) receptor antagonist. 5. The contribution of the IPSP(B) conductance increase to paired-pulse depression of IPSP(A) was evaluated. Paired-pulse depression of IPSP(A) was significantly greater than was the depression of the response to a current pulse delivered 200 ms after the mossy fiber stimulus. In addition. injection of granule cells with GTPgammaS, a nonhydrolyzable guanosine triphosphate (GTP) analogue, occluded both IPSP(B) as well as the effects of baclofen on the granule cell membrane by activating G proteins but did not reduce paired-pulse depression of IPSP(A) or suppression of IPSP(A) by baclofen. Finally, examination of the first and second IPSC(A) evoked by paired stimuli 200 ms apart revealed no significant differences in response kinetics. Taken together, these results indicate that postsynaptic GABA(B) receptors on the granule cells are not responsible for paired-pulse depression of IPSP(A). 6. Monosynaptic IPSPs were evoked by direct stimulation of inhibitory neurons in the inner molecular layer of the dentate gyrus during pharmacological blockade of excitatory transmission with D(-)-2-amino-5-phosphonovaleric acid (D-APV), an N-methyl-D-aspartate (NMDA) receptor antagonist and 6,7-dinitroquinoxaline-2,3-dione (DNQX), a non-NMDA glutamate receptor antagonist. Paired-pulse depression of the monosynaptic IPSP(A) was maximal when stimuli were delivered 200 ms apart and was reversibly antagonized by 2-hydroxy-saclofen (400 muM). Baclofen (10 muM) suppressed the monosynaptic IPSP(A) much less than the mossy fiber-evoked polysynaptic IPSP(A). In contrast, the degree of paired-pulse depression of monosynaptic and polysynaptic IPSP(A)s was not significantly different. 7. A mossy fiber conditioning stimulus markedly reduced mossy fiber-evoked recurrent inhibition of the perforant path-evoked response recorded extracellularly. Suppression of recurrent inhibition was evidenced by an increase in the amplitude of the inhibited population spike. Similarly, a perforant path conditioning stimulus markedly depressed perforant path-evoked paired-pulse inhibition, causing an increase in the amplitude of the inhibited population spike. In both cases, depression of inhibition, and thus enhancement of the population spike, had a time course similar to that for fading of IPSP/C(A) and was blocked by the GABA(B) receptor antagonists, phaclofen (1 mM), 2-hydroxysaclofen (400 muM) or 3-amino-propyl(diethoxymethyl)phosphinic acid (CGP 35348; 400 muM). 8. When perforant path stimulus pairs 10 ms apart were delivered every 200 ms, the enhancement of the granule cell population spike on the second response of each pair resulted in a corresponding increase in the amplitude of the response recorded in area CA3. This increase was maximal when paired stimuli were delivered at frequencies between 2.5 and 10 Hz, corresponding to the range of interstimulus intervals over which disinhibition was maximal. CGP 35348 (400 muM) prevented the loss of paired-pulse inhibition during the train and thus prevented both the increase in population spike amplitude in the granule cell layer as well as the increase in amplitude of the CA3 response. 9. We conclude that activity-dependent depression of mossy fiber-evoked polysynaptic inhibition is mediated by GABA(B) receptors on inhibitory terminals. This GABA(B) receptor-mediated depression of inhibition enhances granule cell firing and thus facilitates signal transmission through the dentate gyrus. However, the time course of the underlying disinhibition causes signal transmission to be enhanced only when stimuli are delivered at frequencies between 2.5 and 10 Hz. Thus the frequency dependence of the disinhibition endows the inhibitory circuits in the dentate gyrus with the ability to filter signals, with transmission selectively enhanced during repetitive activation at frequencies in the range of hippocampal theta rhythm. These results suggest that GABA(B) receptors are a site for pharmacological manipulation of the spread of neural activity.