MUSCARINIC RECEPTORS MEDIATING DEPRESSION AND LONG-TERM POTENTIATION IN RAT HIPPOCAMPUS

1. Two concentration-dependent effects of the muscarinic agonist carba chol (CCh) were characterized in submerged slices of rat hippocampus u sing extracellular recordings of excitatory postsynaptic potentials (E PSPs): muscarinic long-term potentiation (LTP(m)) and depression. 2. L TP(?)m of tile EPSP slope was seen following long exposure (20 min) of the slice to low concentrations of CCh (0.2-0.5 mu M). This LTP(m) wa s not accompanied by a change in the size of the afferent fibre volley or by a change in paired-pulse potentiation, consistent with a postsy naptic locus of CCh action. 3. Intracellular recordings from voltage-c lamped neurons of inward current evoked by iontophoretically applied p ha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl- D-aspartate (NMDA) revealed that, while cellular responses to NMDA ros e transiently upon superfusion with 0.5 mu M CCh, responses to AMPA in creased gradually and remained potentiated after washout of CCh. 4. LT P(m) is mediated by an M2 muscarinic receptor. Two N2 muscarinic recep tor antagonists, methoctramine and AFDX-116, blocked LTP(m). The M2 ag onist oxotremorine induced LTP(m) at low agonist concentrations. None of the M1 and M3 receptor agonists and antagonists tested affected LTP (m). 5. Muscarinic fast onset depression of the EPSP was seen in respo nse to higher concentrations of CCh (2-5 mu M). This depression was ac companied by an increase in paired-pulse potentiation, indicating a po ssible presynaptic locus of action. The M3 muscarinic receptor antagon ist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) blocked t he muscarinic depression of the EPSP slope. M1, M2 and M4 muscarinic a ntagonists did not block this response. 6. Blockade of the muscarinic depression by 4-DAMP did not uncover a suppressed LTP(m). However, add ition of picrotoxin facilitated the expression of LTP(m) induced by hi gh concentrations of CCh, indicating an involvement of interneurons in regulation of LTP(m). 7. Cholinergic denervation produced by fimbria- fornix transection resulted in supersensitivity of both M2- and M3-med iated effects, indicating that the receptors mediating these effects a re not located on presynaptic cholinergic fibres. In the presence of 4 -DAMP and picrotoxin the dose-response curve for CCh-induced effects i n slices from lesioned animals was shifted to the left relative to tha t of normal animals, indicating a supersensitivity of both receptor ty pes.