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. 1996 Oct 15;496(Pt 2):451–470. doi: 10.1113/jphysiol.1996.sp021698

Regulation of EPSPs by the synaptic activation of GABAB autoreceptors in rat hippocampus.

C H Davies 1, G L Collingridge 1
PMCID: PMC1160890  PMID: 8910229

Abstract

1. Intracellular recording was used to study the influence of GABAB autoreceptor-mediated regulation of monosynaptic GABAA and GABAB receptor-mediated hyperpolarizing inhibitory postsynaptic potentials (IPSPAs and IPSPBs, respectively) on alpha-amino-3-hydroxy-5-methyl -4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor-mediated excitatory postsynaptic potentials (EPSPAs and EPSPNs, respectively) in the CA1 region of rat hippocampal slices. To achieve this, synaptic potential were evoked monosynaptically by near stimulation following blockade of either EPSPNs, by the NMDA receptor antagonist (R)-2-amino-5-phosphonopentanoate (AP5; 0.05 mM), or EPSPAs, 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 EPSPAs, which paralleled the time course of paired-pulse depression of monosynaptic IPSCs, and a potentiation of the amplitude (paired-pulse potentiation) of EPSPAs, which did not. Paired-pulse stimulation also caused frequency-dependent changes in EPSPNs. At frequencies > 40 Hz it produced paired-pulse depression of EPSPNs, along with marked summation of IPSPS, and at frequencies < 40 Hz it caused paired-pulsed enlargement of EPSPNs, concomitant with a reduction in IPSPS. 3. Paired-pulse potentiation of EPSPAs at 50 Hz was enhanced by picrotoxin (0.1 mM) but was not significantly affected by 3-amino-propyl(diethoxymethyl)phosphinic acid (CGP 35348; 1 mM). Paired-pulse depression of EPSPNs at 50 Hz was converted to paired-pulse enlargement by picrotoxin but was unaffected by CGP 35348. These effects can be explained by block of IPSPAs by picrotoxin. 4. Paired-pulsed widening of EPSPAs at 5 Hz was occluded by picrotoxin and abolished by CGP 35348. Similarly, paired-pulsed enlargement of EPSPNs at 5 Hz was occluded, and in some cases converted to paired-pulse depression, by picrotoxin. The effects of CGP 35348 were more complex in that this antagonist reduced paired-pulse enlargement of EPSPNs in control medium whereas it eliminated paired-pulsed depression of EPSPNs in the presence of picrotoxin, effects consistent with its block of GABAB autoreceptors and IPSPBS, respectively. 5. 'Priming' using a 'priming stimulation protocol' (a single 'priming stimulus' followed at 1-50 Hz ('priming frequency') by a 'primed burst' of four shocks at 20-100 Hz ('burst frequency')) caused an increase in both 'primed' EPSPAs and EPSPNs compared with 'unprimed' EPSPAs and EPSPNs. This effect was optimal when the respective priming and burst frequencies were 5 and 100 Hz. 6. In the presence of either picrotoxin or CGP 35348 the primed EPSPAs and EPSPNs resembled unprimed EPSPAs and EPSPNs, respectively. This was because picrotoxin occluded whereas CGP 35348 blocked the effect of priming on EPSPS. 7. CGP 35348 had only modest effects on EPSPAs but enhanced EPSPNs evoked by a tetanus (20 stimuli at 100 Hz), in either the presence or absence of picrotoxin. In the absence of picrotoxin, CGP 35348 also promoted depolarization by enhancing a depolarizing GABAA receptor-mediated component (IPSPD). These effects can all be attributed to block of IPSPBS by CGP 35348. 8. CGP 35348 blocked the induction of long-term potentiation (LTP) of extracellularly recorded field EPSPs elicited by a priming stimulation protocol in control medium but was ineffective 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 regulation of AMPA and NMDA receptor-mediated EPSPs during various patterns of synaptic activation caused by the dynamic changes in GABA-mediated synaptic inhibition, which are orchestrated by GABAA autoreceptors in a frequency-dependent

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Selected References

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