title: Facilitation of long-term potentiation by muscarinic M(1) receptors is mediated by inhibition of SK channels.
abstract: Muscarinic receptor activation facilitates the induction of synaptic plasticity and enhances cognitive function. However, the specific muscarinic receptor subtype involved and the critical intracellular signaling pathways engaged have remained controversial. Here, we show that the recently discovered highly selective allosteric M(1) receptor agonist 77-LH-28-1 facilitates long-term potentiation (LTP) induced by theta burst stimulation at Schaffer collateral synapses in the hippocampus. Similarly, release of acetylcholine by stimulation of cholinergic fibers facilitates LTP via activation of M(1) receptors. N-methyl-D-aspartate receptor (NMDAR) opening during theta burst stimulation was enhanced by M(1) receptor activation, indicating this is the mechanism for LTP facilitation. M(1) receptors were found to enhance NMDAR activation by inhibiting SK channels that otherwise act to hyperpolarize postsynaptic spines and inhibit NMDAR opening. Thus, we describe a mechanism where M(1) receptor activation inhibits SK channels, allowing enhanced NMDAR activity and leading to a facilitation of LTP induction in the hippocampus.
authors.affiliation: Medical Research Council Centre for Synaptic Plasticity, School of Physiology and Pharmacology, University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Buchanan
authors.forename: Milos M
authors.initials: MM
authors.lastname: Petrovic
authors.forename: Sophie E L
authors.initials: SE
authors.lastname: Chamberlain
authors.forename: Neil V
authors.initials: NV
authors.lastname: Marrion
authors.forename: Jack R
authors.initials: JR
authors.lastname: Mellor
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D025461:Feedback, Physiological; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009433:Neural Inhibition / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D020239:Receptor Cross-Talk / Q000502:physiology; D043643:Receptor, Muscarinic M1 / Q000187:drug effects* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D015290:Second Messenger Systems / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D013826:Theta Rhythm / Q000502:physiology
chemical_list: C531940:77-LH-28-1; D018721:Muscarinic Agonists; D010880:Piperidines; D015363:Quinolones; D043643:Receptor, Muscarinic M1; D016194:Receptors, N-Methyl-D-Aspartate; D051640:Small-Conductance Calcium-Activated Potassium Channels; D000109:Acetylcholine