title: Muscarinic acetylcholine receptors act in synergy to facilitate learning and memory.
abstract: Understanding how episodic memories are formed and retrieved is necessary if we are to treat disorders in which they malfunction. Muscarinic acetylcholine receptors (mAChR) in the hippocampus and cortex underlie memory formation, but there is conflicting evidence regarding their role in memory retrieval. Additionally, there is no consensus on which mAChR subtypes are critical for memory processing. Using pharmacological and genetic approaches, we found that (1) encoding and retrieval of contextual memory requires mAChR in the dorsal hippocampus (DH) and retrosplenial cortex (RSC), (2) memory formation requires hippocampal M3and cooperative activity of RSC M1and M3,and (3) memory retrieval is more impaired by inactivation of multiple M1-M4mAChR in DH or RSC than inactivation of individual receptor subtypes. Contrary to the view that acetylcholine supports learning but is detrimental to memory retrieval, we found that coactivation of multiple mAChR is required for retrieval of both recently and remotely acquired context memories. Manipulations with higher receptor specificity were generally less potent than manipulations targeting multiple receptor subtypes, suggesting that mAChR act in synergy to regulate memory processes. These findings provide unique insight into the development of therapies for amnestic symptoms, suggesting that broadly acting, rather than receptor-specific, mAchR agonists and positive allosteric modulators may be the most effective therapeutic approach.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, The Asher Center for the Study and Treatment of Depressive Disorders, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Leaderbrand
authors.affiliation: Department of Psychiatry and Behavioral Sciences, The Asher Center for the Study and Treatment of Depressive Disorders, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Chen
authors.affiliation: Department of Psychiatry and Behavioral Sciences, The Asher Center for the Study and Treatment of Depressive Disorders, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Corcoran
authors.affiliation: Department of Psychiatry and Behavioral Sciences, The Asher Center for the Study and Treatment of Depressive Disorders, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Anita L
authors.initials: AL
authors.lastname: Guedea
authors.affiliation: Department of Psychiatry and Behavioral Sciences, The Asher Center for the Study and Treatment of Depressive Disorders, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Jovasevic
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Wess
authors.affiliation: Department of Psychiatry and Behavioral Sciences, The Asher Center for the Study and Treatment of Depressive Disorders, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA j-radulovic@northwestern.edu.
authors.forename: Jelena
authors.initials: J
authors.lastname: Radulovic
mesh_terms: D000818:Animals; D002408:Catheters, Indwelling; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics; D005239:Fear / Q000187:drug effects / Q000502:physiology; D055786:Gene Knockout Techniques; D005822:Genetic Vectors; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007150:Immunohistochemistry; D007858:Learning / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism*; D012601:Scopolamine / Q000494:pharmacology
chemical_list: D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D010890:Pirenzepine; D012601:Scopolamine; C048593:otenzepad