Blockers of adenosine A1, but not muscarinic acetylcholine, receptors improve excessive extracellular glutamate-induced synaptic depression

We investigated adenosinergic and cholinergic effects on excessive glutamate-induced depressions of central excitatory synaptic transmissions in vitro. From the CA1 region in rat hippocampal slices, orthodromically elicited population spikes (PSs) and field excitatory postsynaptic potentials (fEPSPs) at 0.1 Hz were simultaneously recorded. ANOVA was used for statistics, and p < 0.05 was accepted as significant. Glutamate (10 mM for 10 min) completely depressed PSs and fEPSPs, which were partially recovered by the following washout for 40 min (67.5 ± 15.7% and 65.4 ± 13.9% of the control, respectively, p < 0.01, n = 12). The recoveries in PSs and fEPSPs were exacerbated by edrophonium and carbamoylcholine but improved by non- and A1-selective adenosine receptor antagonists (p < 0.01, n = 6). The recovery in PSs, not that in fEPSPs, was exacerbated by adenosine, adenosine A1-receptor agonist and A2a-receptor antagonist (p < 0.01, n = 6). The effects of edrophonium were blocked by non-, M2- and M4-selective muscarinic acetylcholine receptor antagonists (p < 0.01, n = 6). Excessive glutamate depresses glutamatergic excitatory synaptic transmissions, which are exacerbated by muscarinic acetylcholine receptor stimulation but improved by adenosine A1 receptor block. Somatic excitability is impaired by excessive glutamate with adenosine A1 receptor stimulation.

► Excessive glutamate impairs glutamatergic excitatory synaptic transmissions.
► Acetylcholine M2/4 receptor stimulation exacerbates the synaptic impairments.
► Adenosine A1 receptor block improves the synaptic impairments.
► Excessive glutamate alone did not impair somatic excitability.
► Excessive glutamate and adenosine A1 receptor stimulation impair the excitability.