期刊
JOURNAL OF NEUROSCIENCE
卷 29, 期 45, 页码 14271-14286出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3930-09.2009
关键词
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资金
- National Institute of Mental Health (NIMH) [1F32 MH079678-01, 1 F31 MH80559-01]
- National Institute of Neurological Disorders and Stroke
- Vanderbilt Institute of Chemical Biology [T90-DA22873]
- National Institute on Aging
- PhRMA Foundation
- National Institutes of Health [NS30454]
M-1 muscarinic acetylcholine receptors (mAChRs) may represent a viable target for treatment of disorders involving impaired cognitive function. However, a major limitation to testing this hypothesis has been a lack of highly selective ligands for individual mAChR subtypes. We now report the rigorous molecular characterization of a novel compound, benzylquinolone carboxylic acid (BQCA), which acts as a potent, highly selective positive allosteric modulator (PAM) of the rat M-1 receptor. This compound does not directly activate the receptor, but acts at an allosteric site to increase functional responses to orthosteric agonists. Radioligand binding studies revealed that BQCA increases M-1 receptor affinity for acetylcholine. We found that activation of the M-1 receptor by BQCA induces a robust inward current and increases spontaneous EPSCs in medial prefrontal cortex (mPFC) pyramidal cells, effects which are absent in acute slices from M-1 receptor knock-out mice. Furthermore, to determine the effect of BQCA on intact and functioning brain circuits, multiple single-unit recordings were obtained from the mPFC of rats that showed BQCA increases firing of mPFC pyramidal cells in vivo. BQCA also restored discrimination reversal learning in a transgenic mouse model of Alzheimer's disease and was found to regulate non-amyloidogenic APP processing in vitro, suggesting that M-1 receptor PAMs have the potential to provide both symptomatic and disease modifying effects in Alzheimer's disease patients. Together, these studies provide compelling evidence that M-1 receptor activation induces a dramatic excitation of PFC neurons and suggest that selectively activating the M-1 mAChR subtype may ameliorate impairments in cognitive function.
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