Vascular cognitive impairments and neuronal abnormalities in mice

小鼠血管认知障碍和神经元异常

• 批准号: 16300116
• 负责人: YAMADA Masahisa
• 金额: $ 7.1万
• 依托单位: RIKEN
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16300116/
• 关键词: acetylcholine; Muscarinic acetylcholine receptors; cerebral blood flow; neuronal atrophy; ischemia; memory; ムスカリン性受容体; 神経細胞; nitric oxide; 脳底動脈; 脳血管; 認知機能

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.

大量的证据表明，中枢毒蕈碱乙酰胆碱（ACh）受体系统的紊乱在几种病理生理条件下发挥作用，包括阿尔茨海默病和帕金森病，抑郁症，精神分裂症和癫痫。基底前脑中胆碱能神经元的变性是阿尔茨海默病发病机制的核心，并且发生在疾病过程的早期。毒蕈碱型ACh受体在被认为对认知功能重要的前脑区域（如大脑皮层和海马）中大量表达。最近对毒蕈碱受体敲除小鼠的研究揭示了单个毒蕈碱受体亚型（M1-M5）的不同CNS功能。M5毒蕈碱型乙酰胆碱受体（M5 R）已被证明在介导乙酰胆碱依赖性脑血管扩张中起关键作用。我们发现，雄性M5 R-/-小鼠显示脑动脉使用磁共振血管造影在体内的组成性收缩。雄性M5 R-/-小鼠在大脑皮层、海马、基底神经节和丘脑中表现出显著降低的脑血流量（CBF）。来自M5 R-/-小鼠的皮质和海马锥体神经元显示神经元萎缩。M5 R-/-小鼠的海马依赖性空间和非空间记忆也受损。在M5 R-/-小鼠中，CA 3锥体细胞的自发性突触后电流的频率显着衰减，长时程增强在苔藓纤维-CA 3突触显着受损。我们的研究结果表明，受损的M5 R信号可能在脑血管缺陷的病理生理学中发挥作用。M5受体可能代表一个有吸引力的新的治疗靶点，以改善脑血管功能受损引起的记忆缺陷。

项目成果

Vasodilatory effects of cholinergic agonists are greatly diminished in aorta from M3R-/- mice

• DOI: 10.1016/j.ejphar.2004.04.012
• 发表时间: 2004-06-16
• 期刊: EUROPEAN JOURNAL OF PHARMACOLOGY
• 影响因子: 5
• 作者: Khurana, S;Chacon, I;Kennedy, RH
• 通讯作者: Kennedy, RH

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

M5 毒蕈碱乙酰胆碱受体的缺失会导致小鼠脑血管和神经元异常以及认知缺陷

• 发表时间: 2006
• 期刊: Neurobiol Dis 24(2)
• 作者: Araya R;Yamada M et al.
• 通讯作者: Yamada M et al.

Regulation of CD8+ cytolytic T lymphocyte differentiation by a cholinergic pathway

• DOI: 10.1016/j.jneuroim.2005.03.018
• 发表时间: 2005-07
• 期刊: Journal of Neuroimmunology
• 影响因子: 3.3
• 作者: J. Zimring;L. Kapp;M. Yamada;J. Wess;J. Kapp

Functional roles of muscarinic M2 and M3 receptors in mouse stomach motility: studies with muscarinic receptor knockout mice.

• DOI: 10.1016/j.ejphar.2006.10.013
• 发表时间: 2007-01
• 期刊: European journal of pharmacology
• 影响因子: 5
• 作者: T. Kitazawa;K. Hashiba;Jinshan Cao;T. Unno;S. Komori;M. Yamada;J. Wess;T. Taneike

Cholinergic agonist-induced pepsinogen secretion from murine gastric chief cells is mediated by M1 and M3 muscarinic receptors.

• DOI: 10.1152/ajpgi.00105.2004
• 发表时间: 2005-09
• 期刊: American journal of physiology. Gastrointestinal and liver physiology
• 作者: G. Xie;C. Drachenberg;M. Yamada;J. Wess;J. Raufman