Article

Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer's disease

Institut für Neurowissenschaften, Technische Universität München (TUM), 80802 München, Germany.
Science (Impact Factor: 31.48). 10/2008; 321(5896):1686-9. DOI: 10.1126/science.1162844
Source: PubMed

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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    • "Comparing molecular and macro-scale networks is not straightforward ; however, there are studies of both cell function and macroscale networks in the human brain which suggest that gain of co-expression (GOC), a dominant feature in our DC networks, may indicate increased functional activity. For instance, (1) Buckner et al 2009 used functional neuroimaging (fMRI) to demonstrate that the human cortex contains hubs of high functional connectivity correlating with incidence of Ab deposition in AD patients, (2) Ab production is strongly stimulated as a function of increasing neuronal activity (Cirrito et al, 2005), and (3) neuronal activity is highly increased (50% of the neuronal population) in the vicinity of Ab plaques in an early-stage AD mouse model (Busche et al, 2008; Kuchibhotla et al, 2009), with neuronal hyperactive firing in the cortex combined with an increased astrocyte activity and Ab plaques. While gain of transcriptional co-regulation in the brain cortex network may be associated with increased activity surrounding misfolded Ab deposits, it is possible that lack of transcriptional co-regulation (LOC), which is proportionally high in the overlap between AD and HD and high among genes found to be causally related to AD, is associated with upstream events that produce or maintain the misfolded protein aggregates. "
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    • "In a recent study using in vivo 2 photon Ca 2+ imaging in V1 of a mouse model of AD (APP23xPS45), an age-dependent progressive loss of neuronal orientation tuning paralleled the increase in Aí µí»½ load [14]. The orientation tuning defects were limited to neurons with hyperactivity under basal conditions, which are often found in close proximity to Aí µí»½ plaques [16]. Furthermore, the loss of orientation tuning accompanied a progressive deficit in a visual pattern discrimination task [14], which suggests that the neuronal dysfunction may lead to functional decline in visual processing. "
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    • "This can lead the cell to transition more easily to a high-excitation bursting state consisting of sustained firing or bursting at the neuron's saturation rate in synchrony with other connected cells (Fröhlich et al., 2008). This phenomenon has been observed in mouse models of AD, particularly in cells proximal to amyloid plaques, and correlates with the increased incidence of seizures in AD patients (Busche et al., 2008). These pathological states of high excitability, coupled with dysfunctions in Aβ-mediated calcium regulation, lead to greater influx of Ca 2+ into the cell plasma, making the triggering of cell death (apoptosis) more likely. "
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