| Project/Area Number |
16300116
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Nerve anatomy/Neuropathology
|
|---|
| Research Institution | RIKEN |
|---|
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)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
三井 健一 独立行政法人理化学研究所, リサーチリソースセンター, 専門職研究員 (80266030)
|
|---|
| Project Period (FY) |
2004 – 2006
|
| Project Status |
Completed (Fiscal Year 2006)
|
| Budget Amount *help |
¥11,100,000 (Direct Cost: ¥11,100,000)
Fiscal Year 2006: ¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥3,900,000 (Direct Cost: ¥3,900,000)
|
|---|
| Keywords | 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 |
|---|
| 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.
|
