Loss of M5 muscarinic acetylcholine receptors leads to cerebrovascular and neuronal abnormalities and cognitive deficits in mice

Runa Araya, Takanori Noguchi, Munehiro Yuhki, Naohito Kitamura, Makoto Higuchi, Takaomi C. Saido, Kenjiro Seki, Shigeyoshi Itohara, Masako Kawano, Kentaro Tanemura, Akihiko Takashima, Kazuyuki Yamada, Yasushi Kondoh, Iwao Kanno, Jürgen Wess, Masahisa Yamada

Research output: Contribution to journalArticlepeer-review

56 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)334-344
Number of pages11
JournalNeurobiology of Disease
Volume24
Issue number2
DOIs
Publication statusPublished - 2006 Nov

Keywords

  • Cerebral blood flow
  • Cognition
  • Muscarinic acetylcholine receptor
  • Neuronal atrophy

ASJC Scopus subject areas

  • Neurology

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