Loss of M5 muscarinic acetylcholine receptors leads to cerebrovascular and neuronal abnormalities and cognitive deficits in mice.
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.
Araya
Runa
R
Yamada Research Unit, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
Noguchi
Takanori
T
Yuhki
Munehiro
M
Kitamura
Naohito
N
Higuchi
Makoto
M
Saido
Takaomi C
TC
Seki
Kenjiro
K
Itohara
Shigeyoshi
S
Kawano
Masako
M
Tanemura
Kentaro
K
Takashima
Akihiko
A
Yamada
Kazuyuki
K
Kondoh
Yasushi
Y
Kanno
Iwao
I
Wess
Jürgen
J
Yamada
Masahisa
M
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
D043642:Receptor, Muscarinic M5; D000109:Acetylcholine