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

Abstract

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. Alzheimer's disease (AD)1 is a devastating neurodegenerative disorder. Several prominent features consistently found in AD patients include: degeneration of basal forebrain cholinergic neurons and ensuing deficient cholinergic functions in cortex and hippocampus, extracellular protein aggregates containing ␤-amyloid peptides (A␤) in these cholinergic target areas, and impairments in mental functions that are characterized by the loss of memory (1-3). So far, the most effective therapeutic strategy in AD treatment is to enhance cholinergic transmission (4, 5). It has long been recognized that muscarinic acetylcholine receptors (mAChRs) are crucial for the control of high level cognitive processes (6, 7). Drugs that antagonize mAChRs worsen the performance of human subjects and animals in learning and memory tasks (8, 9), while drugs that activate mAChRs are helpful in ameliorating cognitive deficits of AD (10, 11). Despite the discovery of correlation between cholinergic hypofunction and AD, the cellular and molecular mechanisms underlying the function and dysfunction of mAChRs in normal cognition and dementia remain elusive.Prefrontal cortex (PFC), one of the major target areas of basal forebrain cholinergic neurons, has long been associated with high-level, "executive" processes (12), particularly a form of ...

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