Cholinergic modulation of CA1 synapses by the muscarinic M1 receptor subtype in rat hippocampal slices.

Maria Victoria Oberholzer, Edgar Kornisiuk, Francisco Urbano, Carlos Cerveñansky, Denis Servent, and Diana Jerusalinsky Muscarinic antagonists produce amnesia while agonists facilitate memory consolidation when injected into the dorsal hippocampus of rats immediately after training in an inhibitory avoidance task. Muscarinic toxins (MT) 1 and 2 from Dendroaspis angusticeps snake venom act as selective M1 muscarinic receptor agonists and M4 receptor antagonists. MT2 has 4-fold higher affinity for M1 than for M4 receptor. Both toxins improved memory in an one-step inhibitoryavoidance footshock task in rats when injected into the dorsal hippocampus after training. They also enhanced field potentials (fEPSP) at CA1 synapses in rat hippocampal acute slices. This MT2 enhancement of fEPSP was effectively blocked by both atropine (specific though non-selective muscarinic antagonist) and pirenzepine (selective antagonist for M1 and M4 receptors), strongly suggesting the M1 receptor involvement in the phenomenon. Furthermore, scopolamine (specific non-selective muscarinic antagonist) and pirenzepine blocked LTP induction by theta burst stimulation (TBS-LTP) in the same synapses. We used MT7, the most selective M1 antagonist known, to elucidate if the effect of MT1 on fEPSP recorded at CA1 synapses was mediated through M1 receptor subtype and if the receptor blockade by classical muscarinic antagonists was directly responsible for TBS-LTP inhibition. MT7 (10 nM) completely abolished MT1-induced increase in fEPSP and TBS-LTP induction. Taking into account that both MT1 and MT2 have significant affinities for αadrenergic receptors, we also performed radioligand binding assays in rat hippocampal synaptosomal membranes to evaluate MT7 inhibition on binding of both 3H-N-methylscopolamine (3H-NMS, muscarinic ligand) and 3H-prazosin (3HPRZ, α-adrenergic ligand). MT7 inhibited 3H-NMS binding but did not inhibit 3HPRZ binding. Moreover, maximal inhibition of 3H-NMS binding was 38 ± 5%, close to M1 ratio in rat hippocampus. Altogether these results demonstrate that M1 muscarinic receptors positively modulate basal transmission and they are neccesary for LTP induction by TBS at CA1 synapses.

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