Clusters of Hyperactive Neurons Near Amyloid Plaques in a Mouse Model of Alzheimer's Disease
ABSTRACT The neurodegeneration observed in Alzheimer's disease has been associated with synaptic dismantling and progressive decrease in neuronal activity. We tested this hypothesis in vivo by using two-photon Ca2+ imaging in a mouse model of Alzheimer's disease. Although a decrease in neuronal activity was seen in 29% of layer 2/3 cortical neurons, 21% of neurons displayed an unexpected increase in the frequency of spontaneous Ca2+ transients. These "hyperactive" neurons were found exclusively near the plaques of amyloid beta-depositing mice. The hyperactivity appeared to be due to a relative decrease in synaptic inhibition. Thus, we suggest that a redistribution of synaptic drive between silent and hyperactive neurons, rather than an overall decrease in synaptic activity, provides a mechanism for the disturbed cortical function in Alzheimer's disease.
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- "airment in both aMCI and AD mouse models . This view is further supported by data from the double - transgenic APP23 Â PS45 mice , overexpressing the APPswe and PS1G384A mutations ( Sturchler - Pierrat et al . , 1997 ) . These mice show neuronal hyperactivity exclusively near Ab plaques , as was demonstrated by in vivo 2 - photon calcium imaging ( Busche et al . , 2008 ) . Hyperactivity of neurons in the visual cortex of these mice was coupled to defects in neuronal tuning for the orientation of visual stimuli ( Grienberger et al . , 2012 ) . Interestingly , the fraction of hyperactive neurons was already dramatically increased in the CA1 area before the onset of plaque pathology , compared with contr"
ABSTRACT: Neuronal activity directly promotes the production and secretion of amyloid β (Aβ). Interestingly, neuronal hyperactivity can be observed in presymptomatic stages of both sporadic and familial Alzheimer's disease (AD) and in several AD mouse models. In this review, we will highlight the recent evidence for neuronal hyperactivity before or during the onset of cognitive defects in mild cognitive impairment. Furthermore, we review specific molecular mechanisms through which neuronal hyperactivity affects Aβ production and degradation. With these data, we will provide more insight into the 2-faced nature of neuronal hyperactivity: does enhanced neuronal activity during the presymptomatic stages of AD provide protection against the earliest disease processes or is it a pathogenic contributor to AD? Copyright © 2014 Elsevier Inc. All rights reserved.Neurobiology of Aging 09/2014; 36(1). DOI:10.1016/j.neurobiolaging.2014.08.014 · 5.01 Impact Factor
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- "Since neuronal excitability has been associated with synaptic plasticity, learning and memory32 and a disturbance in equilibrium between silent and hyperactive neurons has been shown in AD mouse brain12, we investigated the effects of NTR1 onto intrinsic excitability of pyramidal neurons in the hippocampal CA1 region, an area critically involved in memory formation. In coronal brain slices from mice of 2–3 months of age, spontaneous action potential (sAPs) of hippocampal CA1 pyramidal neurons were recorded without intermittency using the whole cell patch clamp technique. "
ABSTRACT: Neurodegeneration and synaptic dysfunction observed in Alzheimer's disease (AD) have been associated with progressive decrease in neuronal activity. Here, we investigated the effects of Notoginsenoside R1 (NTR1), a major saponin isolated from Panax notoginseng, on neuronal excitability and assessed the beneficial effects of NTR1 on synaptic and memory deficits under the Aβ-enriched conditions in vivo and in vitro. We assessed the effects of NTR1 on neuronal excitability, membrane ion channel activity, and synaptic plasticity in acute hippocampal slices by combining electrophysiological extracellular and intracellular recording techniques. We found that NTR1 increased the membrane excitability of CA1 pyramidal neurons in hippocampal slices by lowering the spike threshold possibly through a mechanism involving in the inhibition of voltage-gated K(+) currents. In addition, NTR1 reversed Aβ1-42 oligomers-induced impairments in long term potentiation (LTP). Reducing spontaneous firing activity with 10 nM tetrodotoxin (TTX) abolished the protective effect of NTR1 against Aβ-induced LTP impairment. Finally, oral administration of NTR1 improved the learning performance of the APP/PS1 mouse model of AD. Our work reveals a novel mechanism involving in modulation of cell strength, which contributes to the protective effects of NTR1 against Aβ neurotoxicity.Scientific Reports 09/2014; 4:6352. DOI:10.1038/srep06352 · 5.58 Impact Factor
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- "Interestingly, aged mice exhibited increased microglial soma movement in comparison to younger mice, but this effect was diminished in response to acute injury by laser lesion . Under pathological conditions, such as AD and in mouse models of AD, microglial cells are tightly associated with and cluster around dense core amyloid plaques , which are the major neuropathological hallmark of AD and are thought to be toxic to the surrounding neural tissue [17, 67, 82, 83, 112]. In terms of morphology, microglia display a reactive phenotype in AD with typically short, thickened and less ramified processes [54, 81, 116]. "
ABSTRACT: Microglia, the tissue-resident macrophages of the brain, are attracting increasing attention as key players in brain homeostasis from development through aging. Recent works have highlighted new and unexpected roles for these once-enigmatic cells in both healthy central nervous system function and in diverse pathologies long thought to be primarily the result of neuronal malfunction. In this review, we have chosen to focus on Rett syndrome, which features early neurodevelopmental pathology, and Alzheimer's disease, a disorder associated predominantly with aging. Interestingly, receptor-mediated microglial phagocytosis has emerged as a key function in both developmental and late-life brain pathologies. In a mouse model of Rett syndrome, bone marrow transplant and CNS engraftment of microglia-like cells were associated with surprising improvements in pathology-these benefits were abrogated by block of phagocytic function. In Alzheimer's disease, large-scale genome-wide association studies have been brought to bear as a method of identifying previously unknown susceptibility genes, which highlight microglial receptors as promising novel targets for therapeutic modulation. Multi-photon in vivo microscopy has provided a method of directly visualizing the effects of manipulation of these target genes. Here, we review the latest findings and concepts emerging from the rapidly growing body of literature exemplified for Rett syndrome and late-onset, sporadic Alzheimer's disease.Acta Neuropathologica 07/2014; 128(3). DOI:10.1007/s00401-014-1321-z · 10.76 Impact Factor