REGULATION OF EPSPS BY THE SYNAPTIC ACTIVATION OF GABA(B) AUTORECEPTORS IN RAT HIPPOCAMPUS

1. Intracellular recording was used to study the influence of GABA(B) autoreceptor-mediated regulation of monosynaptic GABA(A) and GABA(B) r eceptor-mediated hyperpolarizing inhibitory postsynaptic potentials (I PSP(A)s and IPSP(B)s, respectively) on lpha-amino-3-hydroxy-5-methyl-4 -isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) recept or-mediated excitatory postsynaptic potentials (EPSP(A)s and EPSP(N)s, respectively) in the CA1 region of rat hippocampal slices. To achieve this, synaptic potentials were evoked monosynaptically by near stimul ation following blockade of either EPSP(N)s, by the NMDA receptor anta gonist (R)-2-amino-5-phosphonopentanoate (AP5; 0.05 mM), or EPSP(A)s, by the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3 -dione (CNQX; 0.01 mM). 2. Paired-pulse stimulation at 3-50 Hz caused an increase in the duration (paired-pulse widening) of EPSP(A)s, which paralleled the time course of paired-pulse depression of monosynaptic IPSCs, and a potentiation of the amplitude (paired-pulse potentiation ) of EPSP(A)s, which did not. Paired-pulse stimulation also caused fre quency-dependent changes in EPSP(N)s. At frequencies >40 Hz it produce d paired-pulse depression of EPSP(N)s, along with marked summation of IPSPs, and at frequencies <40 Hz it caused paired-pulse enlargement of EPSP(N)s, concomitant with a reduction in IPSPs. 3. Paired-pulse pote ntiation of EPSP(A)s at 50 Hz was enhanced by picrotoxin (0.1 mM) but was not significantly affected by 3-amino-propyl(diethoxymethyl)phosph inic acid (CGP 35348; 1 mM). Paired-pulse depression of EPSP(N)s at 50 Hz was converted to paired-pulse enlargement by picrotoxin but was un affected by CGP 35348. These effects can be explained by block of IPSP (A)s by picrotoxin. 4. Paired-pulse widening of EPSP(A)s at 5 Hz was o ccluded by picrotoxin and abolished by CGP 35348. Similarly, paired-pu lse enlargement of EPSP(N)s at 5 Hz was occluded, and in some cases co nverted to paired-pulse depression, by picrotoxin. The effects of CGP 35348 were more complex in that this antagonist reduced paired-pulse e nlargement of EPSP(N)s in control medium whereas it eliminated paired- pulse depression of EPSP(N)s in the presence of picrotoxin, effects co nsistent with its block of GABA(B) autoreceptors and IPSP(B)s, respect ively.5. 'Priming' using a 'priming stimulation protocol' (a single 'p riming stimulus' followed at 1-50 Hz ('priming frequency') by a 'prime d burst' of four shocks at 20-100 Hz ('burst frequency')) caused an in crease in both 'primed' EPSP(A)s and EPSP(N)s compared with 'unprimed' EPSP(A)s and EPSP(N)s. This effect was optimal when the respective pr iming and burst frequencies were 5 and 100 Hz.6. In the presence of ei ther picrotoxin or CGP 35348 the primed EPSP(A)s and EPSP(A)s resemble d unprimed EPSP(A)s and EPSP(N)s, respectively. This was because picro toxin occluded whereas CGP 35348 blocked the effect of priming on EPSP s. 7. CGP 35348 had only modest effects on EPSP(A)s but enhanced EPSP( N)s evoked by a tetanus (20 stimuli at 100 Hz), in either tile presenc e or absence of picrotoxin. In the absence of picrotoxin, CGP 35348 al so promoted depolarization by enhancing a depolarizing GABA(A) recepto r-mediated component (IPSPD). These effects can all be attributed to b lock of IPSP(B)s by CGP 35348. 8. CGP 35348 blocked the induction of l ong-term potentiation (LTP) of extracellularly recorded field EPSPs el icited by a priming stimulation protocol in control medium but was ine ffective in the presence of picrotoxin. CGP 35348 was also ineffective at preventing tetanus-induced LTP (100 Hz, 1 s), in both the absence and presence of picrotoxin. 9. These data demonstrate the complex regu lation of AMPA and NMDA receptor-mediated EPSPs during various pattern s of synaptic activation caused by the dynamic changes in GABA-mediate d synaptic inhibition, which are orchestrated by GABA(B) autoreceptors in a frequency-dependent manner.