title: Loss of M5 muscarinic acetylcholine receptors leads to cerebrovascular and neuronal abnormalities and cognitive deficits in mice.
abstract: The M5 muscarinic acetylcholine receptor (M5R) has been shown to play a crucial role in mediating acetylcholine-dependent dilation of cerebral blood vessels. We show that male M5R-/- mice displayed constitutive constriction of cerebral arteries using magnetic resonance angiography in vivo. Male M5R-/- mice exhibited a significantly reduced cerebral blood flow (CBF) in the cerebral cortex, hippocampus, basal ganglia, and thalamus. Cortical and hippocampal pyramidal neurons from M5R-/- mice showed neuronal atrophy. Hippocampus-dependent spatial and nonspatial memory was also impaired in M5R-/- mice. In M5R-/- mice, CA3 pyramidal cells displayed a significantly attenuated frequency of the spontaneous postsynaptic current and long-term potentiation was significantly impaired at the mossy fiber-CA3 synapse. Our findings suggest that impaired M5R signaling may play a role in the pathophysiology of cerebrovascular deficits. The M5 receptor may represent an attractive novel therapeutic target to ameliorate memory deficits caused by impaired cerebrovascular function.
authors.affiliation: Yamada Research Unit, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Runa
authors.initials: R
authors.lastname: Araya
authors.forename: Takanori
authors.initials: T
authors.lastname: Noguchi
authors.forename: Munehiro
authors.initials: M
authors.lastname: Yuhki
authors.forename: Naohito
authors.initials: N
authors.lastname: Kitamura
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
authors.forename: Takaomi C
authors.initials: TC
authors.lastname: Saido
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Seki
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Itohara
authors.forename: Masako
authors.initials: M
authors.lastname: Kawano
authors.forename: Kentaro
authors.initials: K
authors.lastname: Tanemura
authors.forename: Akihiko
authors.initials: A
authors.lastname: Takashima
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Yamada
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kondoh
authors.forename: Iwao
authors.initials: I
authors.lastname: Kanno
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
authors.forename: Masahisa
authors.initials: M
authors.lastname: Yamada
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000378:metabolism* / Q000503:physiopathology; D002536:Cerebral Arteries / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000235:genetics; D002561:Cerebrovascular Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017774:Long-Term Potentiation / Q000235:genetics; D018810:Magnetic Resonance Angiography; D008297:Male; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D017966:Pyramidal Cells / Q000378:metabolism / Q000473:pathology; D043642:Receptor, Muscarinic M5 / Q000235:genetics*; D009435:Synaptic Transmission / Q000235:genetics; D014661:Vasoconstriction / Q000235:genetics
chemical_list: D043642:Receptor, Muscarinic M5; D000109:Acetylcholine