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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholine / metabolism
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Animals
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Brain / blood supply
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Brain / metabolism*
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Brain / physiopathology
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Cerebral Arteries / metabolism*
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Cerebral Arteries / pathology
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Cerebral Arteries / physiopathology
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Cerebral Cortex / metabolism
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Cerebral Cortex / pathology
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Cerebral Cortex / physiopathology
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Cerebrovascular Circulation / genetics
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Cerebrovascular Disorders / genetics
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Cerebrovascular Disorders / metabolism*
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Cerebrovascular Disorders / physiopathology
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Cognition Disorders / genetics
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Cognition Disorders / metabolism*
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Cognition Disorders / physiopathology
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Disease Models, Animal
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Hippocampus / metabolism
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Hippocampus / pathology
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Hippocampus / physiopathology
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Long-Term Potentiation / genetics
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Magnetic Resonance Angiography
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Male
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Memory Disorders / genetics
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Memory Disorders / metabolism
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Memory Disorders / physiopathology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Nerve Degeneration / genetics
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Nerve Degeneration / metabolism
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Nerve Degeneration / pathology
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Neurodegenerative Diseases / genetics
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Neurodegenerative Diseases / metabolism*
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Neurodegenerative Diseases / physiopathology
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Pyramidal Cells / metabolism
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Pyramidal Cells / pathology
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Receptor, Muscarinic M5 / genetics*
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Synaptic Transmission / genetics
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Vasoconstriction / genetics
Substances
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Receptor, Muscarinic M5
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Acetylcholine