title: Activation of Muscarinic M1 Acetylcholine Receptors Induces Long-Term Potentiation in the Hippocampus.
abstract: Muscarinic M1 acetylcholine receptors (M1Rs) are highly expressed in the hippocampus, and their inhibition or ablation disrupts the encoding of spatial memory. It has been hypothesized that the principal mechanism by which M1Rs influence spatial memory is by the regulation of hippocampal synaptic plasticity. Here, we use a combination of recently developed, well characterized, selective M1R agonists and M1R knock-out mice to define the roles of M1Rs in the regulation of hippocampal neuronal and synaptic function. We confirm that M1R activation increases input resistance and depolarizes hippocampal CA1 pyramidal neurons and show that this profoundly increases excitatory postsynaptic potential-spike coupling. Consistent with a critical role for M1Rs in synaptic plasticity, we now show that M1R activation produces a robust potentiation of glutamatergic synaptic transmission onto CA1 pyramidal neurons that has all the hallmarks of long-term potentiation (LTP): The potentiation requires NMDA receptor activity and bi-directionally occludes with synaptically induced LTP. Thus, we describe synergistic mechanisms by which acetylcholine acting through M1Rs excites CA1 pyramidal neurons and induces LTP, to profoundly increase activation of CA1 pyramidal neurons. These features are predicted to make a major contribution to the pro-cognitive effects of cholinergic transmission in rodents and humans.
authors.affiliation: Neuroscience, Eli Lilly & Company, Windlesham, Surrey GU20 6PH, UK.
authors.forename: Siobhan H
authors.initials: SH
authors.lastname: Dennis
authors.affiliation: Neuroscience, Eli Lilly & Company, Windlesham, Surrey GU20 6PH, UK.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pasqui
authors.affiliation: Neuroscience, Eli Lilly & Company, Windlesham, Surrey GU20 6PH, UK.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Colvin
authors.affiliation: Neuroscience, Eli Lilly & Company, Windlesham, Surrey GU20 6PH, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Sanger
authors.affiliation: Neuroscience, Eli Lilly & Company, Windlesham, Surrey GU20 6PH, UK.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Mogg
authors.affiliation: Neuroscience, Eli Lilly & Company, Indianapolis, IN 46285, USA.
authors.forename: Christian C
authors.initials: CC
authors.lastname: Felder
authors.affiliation: Neuroscience, Eli Lilly & Company, Windlesham, Surrey GU20 6PH, UK.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Broad
authors.affiliation: Neuroscience, Eli Lilly & Company, Windlesham, Surrey GU20 6PH, UK School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Steve M
authors.initials: SM
authors.lastname: Fitzjohn
authors.affiliation: Neuroscience, Eli Lilly & Company, Windlesham, Surrey GU20 6PH, UK.
authors.forename: John T R
authors.initials: JT
authors.lastname: Isaac
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Jack R
authors.initials: JR
authors.lastname: Mellor
mesh_terms: D000818:Animals; D018678:Cholinergic Agents / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects; D043643:Receptor, Muscarinic M1 / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D018678:Cholinergic Agents; D043643:Receptor, Muscarinic M1
keywords: CA1; hippocampus; long-term potentiation; muscarinic m1 receptor; synaptic plasticity