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J. Biol. Chem., Vol. 278, Issue 29, 26888-26896, July 18, 2003

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Impaired Modulation of GABAergic Transmission by Muscarinic Receptors in a Mouse Transgenic Model of Alzheimer's Disease^*

Ping Zhong, Zhenglin Gu, Xun Wang, Houbo Jiang, Jian Feng and Zhen Yan 

From the Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York 14214

It has long been recognized that muscarinic acetylcholine receptors (mAChRs) are crucial for the control of cognitive processes, and drugs that activate mAChRs are helpful in ameliorating cognitive deficits of Alzheimer's disease (AD). On the other hand, GABAergic transmission in prefrontal cortex (PFC) plays a key role in "working memory" via controlling the timing of neuronal activity during cognitive operations. To test whether the muscarinic and -aminobutyric acid (GABA) system are interconnected in normal cognition and dementia, we examined the muscarinic regulation of GABAergic transmission in PFC of an animal model of AD. Transgenic mice overexpressing a mutant gene for -amyloid precursor protein (APP) show behavioral and histopathological abnormalities resembling AD and, therefore, were used as an AD model. Application of the mAChR agonist carbachol significantly increased the spontaneous inhibitory postsynaptic current (sIPSC) frequency and amplitude in PFC pyramidal neurons from wild-type animals. In contrast, carbachol failed to increase the sIPSC amplitude in APP transgenic mice, whereas the carbachol-induced increase of the sIPSC frequency was not significantly changed in these mutants. Similar results were obtained in rat PFC slices pretreated with the -amyloid peptide (A). Inhibiting protein kinase C (PKC) blocked the carbachol enhancement of sIPSC amplitudes, implicating the PKC dependence of this mAChR effect. In APP transgenic mice, carbachol failed to activate PKC despite the apparently normal expression of mAChRs. These results show that the muscarinic regulation of GABA transmission is impaired in the AD model, probably due to the A-mediated interference of mAChR activation of PKC.

Received for publication, March 19, 2003 , and in revised form, April 10, 2003.

^* This work was supported by National Institutes of Health Grants AG21923 (to Z. Y.), MH63128 (to Z. Y.), National Science Foundation Grant IBN-0117026 (to Z. Y.), and Howard Hughes Medical Institute Biomedical Research Support Program Grant 53000261 (State University of New York at Buffalo). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Physiology and Biophysics, State University of New York at Buffalo, 124 Sherman Hall, Buffalo, NY 14214. E-mail: zhenyan{at}buffalo.edu.

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