Muscarinic Cholinergic Modulation of Long-Lasting Synaptic Plasticity in the Rat Dentate Gyrus

Abstract : The effects of muscarinic cholinergic receptor activation on the induction of long-lasting synaptic plasticity were investigated in an in vitro tissue slice preparation of dentate gyrus from rat hippocampus. Responses evoked by stimulation of medial perforant path axons were measured using extracellular microelectrodes positioned in either or both the granule cell layer and the mid-molecular layer of the dentate gyrus. Two examples of long-lasting synaptic plasticity of medial perforant path/granule cell synapses were studied. The first, long-term potentiation (LTP), was induced by application of a high-frequency stimulus train to the medial perforant path, and was measured as a long-lasting increase in synaptic efficacy at these synapses. The second, beta-adrenergic- induced long-lasting potentiation (LLP), was induced by perfusion of slices with artificial cerebrospinal fluid containing either norepinephrine or isoproterenol, and was also measured as a long-lasting increase in synaptic function. The induction of both LTP and LLP was found to be dependent on activation of N-methyl-D-aspartate (NMDA) receptors.The nonselective muscarinic receptor agonist, muscarine, produced a concentration-dependent depression of evoked responses in the dentate gyrus. At a low concentration (1 micro M) that had no effect on evoked responses, muscarine facilitated induction of LTP, but not LLP. This facilitation was prevented by pirenzepine, an Ml muscarinic receptor antagonist. At a higher concentration of muscarine (10 micro M) that depressed evoked responses, LTP was not facilitated, and LLP was blocked. The depression of evoked responses produced by 10 micro M muscarine was not prevented by pretreatment with pertussis toxin, and was blocked by atropine. The muscarinic receptor subtype-selective antagonists pirenzepine (Ml), AFDX-116 (M2), and 4-DAMP (M3/M1) all competitively antagonized muscarinic depression of evoked responses, with 4-DAMP exhibiting the greatest potency.