GABAergic transmission in the hippocampus can be modulated by several presynaptic heteroreceptors, including mGlu, GABA_B and kainate receptors, which detect transmitter release from intrinsic neurons. However, the hippocampus also receives afferents from other structures, which may also influence synaptic transmission via heteroreceptors. Here we report that α7-nicotinic receptors (nAChRs) can modulate GABA_A receptor-mediated signalling in the rodent hippocampus.

We obtained hippocampal slices from guinea-pigs killed by cervical dislocation. CA1 pyramidal cells and stratum radiatum interneurons were recorded in whole-cell voltage-clamp mode in the presence of antagonists of AMPA, kainate, NMDA, group III mGlu and GABA_B receptors. Stimuli were delivered to stratum radiatum to isolate GABA_A receptor-mediated IPSCs.

Application of the α7-nAChR agonist choline (1 mM) produced a reversible depression of the IPSC amplitude to 78 ± 2 % (mean ± S.E.M., P < 0.01, paired t test, n = 5) and 84 ± 3 % (P < 0.01, n = 6) of baseline in interneurons and pyramidal cells, respectively. Similar results were obtained with another α7-nAChR agonist, 4OH-GTS-21 (3 µM). In order to test whether endogenous ACh, released from cholinergic afferent fibres, could reproduce these effects, we delivered tetanic stimuli (20 pulses, 100 Hz) to stratum oriens. This resulted in a long-lasting (10 min) depression of the evoked IPSCs (86 ± 4 % of baseline: P < 0.01; n = 8). We confirmed that this effect was mediated by acetylcholine release acting on α7-nAChRs by demonstrating that it could be potentiated by application of the acetylcholine cholinesterase inhibitor eserine (n = 8), and abolished by the α7-nAChR antagonist methyllycaconitine (n = 8).

ACh-mediated depression of IPSCs in CA1 neurons provides a powerful method of modulating hippocampal excitability and may contribute to cholinergic effects on learning and memory.

We are grateful to Dr R.L. Papke for the gift of 4OH-GTS-21.