title: M1 muscarinic receptors boost synaptic potentials and calcium influx in dendritic spines by inhibiting postsynaptic SK channels.
abstract: Acetylcholine release and activation of muscarinic cholinergic receptors (mAChRs) enhance synaptic plasticity in vitro and cognition and memory in vivo. Within the hippocampus, mAChRs promote NMDA-type glutamate receptor-dependent forms of long-term potentiation. Here, we use calcium (Ca) imaging combined with two-photon laser glutamate uncaging at apical spines of CA1 pyramidal neurons to examine postsynaptic mechanisms of muscarinic modulation of glutamatergic transmission. Uncaging-evoked excitatory postsynaptic potentials and Ca transients are increased by muscarinic stimulation; however, this is not due to direct modulation of glutamate receptors. Instead, mAChRs modulate a negative feedback loop in spines that normally suppresses synaptic signals. mAChR activation reduces the Ca sensitivity of small conductance Ca-activated potassium (SK) channels that are found in the spine, resulting in increased synaptic potentials and Ca transients. These effects are mediated by M1-type muscarinic receptors and occur in a casein kinase-2-dependent manner. Thus, muscarinic modulation regulates synaptic transmission by tuning the activity of nonglutamatergic postsynaptic ion channels.
authors.affiliation: Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Giessel
authors.forename: Bernardo L
authors.initials: BL
authors.lastname: Sabatini
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D047390:Casein Kinase II / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism*; D025461:Feedback, Physiological; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D017966:Pyramidal Cells / Q000166:cytology / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000502:physiology*; D043643:Receptor, Muscarinic M1 / Q000378:metabolism*; D015290:Second Messenger Systems / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D055366:Synaptic Potentials / Q000502:physiology
chemical_list: D043643:Receptor, Muscarinic M1; D051640:Small-Conductance Calcium-Activated Potassium Channels; D047390:Casein Kinase II; D000109:Acetylcholine; D002118:Calcium