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2006 Fiscal Year Final Research Report Summary

Vascular cognitive impairments and neuronal abnormalities in mice

Research Project

Project/Area Number 16300116
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Nerve anatomy/Neuropathology
Research InstitutionRIKEN

Principal Investigator

YAMADA Masahisa  RIKEN, Yamada Research Unit, Unit Leader, 山田研究ユニット, ユニットリーダー (60321832)

Project Period (FY) 2004 – 2006
Keywordsacetylcholine / Muscarinic acetylcholine receptors / cerebral blood flow / neuronal atrophy / ischemia / memory
Research Abstract

A considerable body of evidence indicates that disturbances in the central muscarinic acetylcholine (ACh) receptor system play a role in several pathophysiologic conditions, including Alzheimer's and Parkinson's disease, depression, schizophrenia, and epilepsy. Degeneration of cholinergic neurons in the basal forebrain is central to the pathogenesis of Alzheimer's disease and occurs early in the disease process. Muscarinic ACh receptors are abundantly expressed in forebrain areas thought to be important for cognitive functions, such as the cerebral cortex and hippocampus. Recent studies with muscarinic receptor knockout mice have revealed distinct CNS functions for the individual muscarinic receptor subtypes (M1-M5). 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 non-spatial 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 playa 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.

  • Research Products

    (18 results)

All 2007 2006 2005 2004

All Journal Article (18 results)

  • [Journal Article] Functional roles of muscarinic M(2) and M(3) receptors in mouse stomach motility : Studies with muscarinic receptor knockout mice2007

    • Author(s)
      Kitazawa T, Yamada M et al.
    • Journal Title

      Eur J Pharmacol. 554

      Pages: 212-222

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Functional roles of muscarinic M(2) and M(3) receptors in mouse stomach motility : Studies with muscarinic receptor knockout mice2007

    • Author(s)
      Kitazawa T, Yamada M et al.
    • Journal Title

      Eur J Pharmacol 554

      Pages: 212-222

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Loss of M5 muscarinic acetylcholine receptors leads to cerebrovascular and neuronal abnormalities and cognitive deficits in mice2006

    • Author(s)
      Araya R, Yamada M et al.
    • Journal Title

      Neurobiol Dis. 24(2)

      Pages: 334-344

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Roles of M(2) and M(3) muscarinic receptors in cholinergic nerve-induced contractions in mouse ileum studied with receptor knockout mice2006

    • Author(s)
      Unno T, Yamada M et al.
    • Journal Title

      Br J Pharmacol. 149

      Pages: 1022-1030

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Los of M5 muscarinic acetylcholine receptors leads to cerebrovascular and neuronal abnormalities and cognitive deficits in mice2006

    • Author(s)
      Araya R, Yamada M et al.
    • Journal Title

      Neurobiol Dis 24(2)

      Pages: 334-344

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Roles of M(2) and M(3)muscarinic receptors in cholinergic nerve-induced contractions in mouse ileum studied with receptor knockout mice2006

    • Author(s)
      Unno T, Yamada M et.sl
    • Journal Title

      Br J pharmacol 149

      Pages: 1022-1030

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Paradoxical sleep in mice lacking M3 and M2/M4 muscarinic receptors.2005

    • Author(s)
      Goutagny et al.
    • Journal Title

      Neuropsychobiology. 52

      Pages: 140-146

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] M_2 and M_3 muscarinic receptor-mediated contractions in longitudinal smooth muscle of the ileum studied with receptor knockout mice.2005

    • Author(s)
      Unno et al.
    • Journal Title

      Br J Pharmacol 146

      Pages: 98-108

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Deoxycholyltaurine-induced vasodilation of rodent aorta is nitric oxide- and muscarinic M_3 recentor-dependent2005

    • Author(s)
      Khurana et al.
    • Journal Title

      Eur J Pharmacol 517

      Pages: 103-110

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Cholinergic agonist-induced pepsinogen secretion from murine gastric chief cells is mediated by M_1 and M_3 muscarinic receptors2005

    • Author(s)
      Xie et al.
    • Journal Title

      Am J Physiol Gastrointest Liver Physiol. 289

      Pages: G521-G529

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Paradoxical sleep in mice lacking M3 and M2/M4 muscarinic receptors.2005

    • Author(s)
      Goutagny et al.
    • Journal Title

      Neuropsychobiology 52

      Pages: 140-146

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] M_2 and M_3 muscarinic receptor-mediated contractions in longitudinal smooth muscle of the ileum studied with receptor knockout mice2005

    • Author(s)
      Unno et al.
    • Journal Title

      Br J pharmacol 146

      Pages: 98-108

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Deoxycholyltaurine-induced vasodilation of rodent aorta is nitric oxide-and muscarinic M_3 receptor-dependent2005

    • Author(s)
      Khurana et al.
    • Journal Title

      Eur J pharmacol 157

      Pages: 103-110

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Cholinergic agonist-induced pepsinogen secretion from murine gastric chief cells is mediated by M_1 and M_3 muscarinic receptors2005

    • Author(s)
      Xie et al.
    • Journal Title

      Am J Physiol Gastrointest Liver Physiol 289

      Pages: G521-G529

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Vasodilatory effects of cholinergic agonists are greatly diminished in aorta from M3R-/-mice.2004

    • Author(s)
      Khurana et al.
    • Journal Title

      Eur J Pharmacol 493

      Pages: 127-132

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Ventilatory pattern and chemosensitivity in M1 and M3 muscarinic receptor knockout mice.2004

    • Author(s)
      Boudinot et al.
    • Journal Title

      Respir Physiol Neurobiol 139

      Pages: 237-245

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Loss of vagally mediated bradycardia and bronchoconstriction in mice lacking M2 or M3 muscarinic acetylcholine receptors.2004

    • Author(s)
      Fisher et al.
    • Journal Title

      FASEB J 18

      Pages: 711-713

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Ventilatory pattern and chemosensitibity in M1 and M3 muscarinic receptor knockout mice.2004

    • Author(s)
      Boudinot et al.
    • Journal Title

      Respir Physiol Neurobiol 139

      Pages: 237-245

    • Description
      「研究成果報告書概要(欧文)」より

URL: 

Published: 2008-05-27  

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