1. Intracellular recording techniques were used to study the effects of repetitive stimulation on monosynaptically activated inhibitory postsynaptic currents (IPSCs) in rat hippocampal slices. This was achieved by stimulation in stratum radiatum close to a recorded CA1 pyramidal neurone after pharmacological blockade of excitatory synaptic responses, using a combination of the N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonists D-2-amino-5-phosphonopentanoate (AP5; 0.04-0.1 mm) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 0.02-0.04 mm), respectively. 2. Fixed-intensity stimulation at frequencies of less than 0.1 Hz evoked biphasic IPSCs of constant amplitude and waveform. In contrast, when two shocks (paired pulse) or longer trains of ten or more stimuli (i.e. tetani) were delivered at frequencies of between 0.2 and 20 Hz there was marked depression of both phases of every IPSC (by 60-100%) relative to the first or 'priming' IPSC evoked. 3. The gamma-aminobutyric acid (GABA)B receptor antagonists phaclofen (0.4-2 mm), 2-hydroxy-saclofen (0.02-0.4 mm) and 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP 35348; 0.01-1 mm) reduced or abolished, in a concentration-dependent and reversible manner, both the late phase of the IPSC (IPSC(B)) and paired-pulse depression of the early phase of the IPSC (IPSC(A)). Expressed in terms of IC50 values, all three antagonists were 5-10 times more potent at blocking IPSC(B) than paired-pulse depression. 4. Paired-pulse depression, at 5 and 10 Hz, has been shown to be mediated by GABA acting on presynaptic GABA(B) receptors (i.e. GABA(B) autoreceptors). We now show that GABA(B) receptor antagonists reverse paired-pulse depression over the entire range of frequencies (0.1-50 Hz) that it occurs. 5. GABA(B) receptor antagonists reversed substantially the depression of IPSCs during tetani delivered at 5 or 10 Hz. However at 20 Hz, GABA(B) receptor antagonists appeared to be less effective. At 100 Hz they appeared to be ineffective at reversing the depression of IPSC(A); since the antagonists block IPSC(B) the net effect was to reduce the level of outward current. 6. At frequencies of 20 Hz or more, there was also the appearance of a slow inward current which increased in size in proportion to the frequency and number of shocks in the tetanus. This current (termed here IPSC(I)) was more pronounced at hyperpolarized membrane potentials and was blocked by picrotoxin (0.1 mm) or bicuculline (0.05 mm). 7. 'Priming' is considered to represent a more physiological pattern of activity than a tetanus. We have investigated the effects of GABA(B) receptor antagonists on IPSCs evoked by a 'priming stimulation protocol'; this comprised a single shock ('priming stimulus') followed after 0.2 s by four shocks at 100 Hz ('primed burst'). 'Priming' reduces the size of IPSC(A) and IPSC(B) evoked by the 'primed burst' and limits the appearance of IPSC(I). 8. GABA(B) receptor antagonists reversed substantially the depression of IPSC(A)s induced by the 'priming stimulus'. They also promoted the appearance of IPSC(I). 9. Under control conditions the depression of IPSCs during the 'primed-burst' response is offset by facilitation of the amplitude of IPSCs. In addition the second and subsequent IPSC(A)s within a 'primed burst' had a longer duration than the initial 'primed' IPSC(A) (which was similar to the 'priming' IPSC(A)). 10. In the presence of GABA(B) receptor antagonists there was no facilitation of the amplitude of IPSC(A)s but the increase in duration still occurred. 11. The facilitation of the amplitude of IPSCs during the 'primed burst' was similar for both IPSC(A) and IPSC(B). 12. In summary, a process initiated by the activation of GABA(B) autoreceptors can account largely for depression of a single IPSC and brief bursts of IPSCs caused by a single 'priming stimulus'. However, with a high-frequency tetanus the GABA(B) autoreceptor-driven mechanism is compensated by facilitation of depressed IPSCs, which in turn promotes the appearance of IPSC(I). This compensatory mechanism provides a further level of complexity to the dynamic changes in synaptic inhibition.
