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.
- SourceAvailable from: Jun Zhu
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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. "
ABSTRACT: Using expression profiles from postmortem prefrontal cortex samples of 624 dementia patients and non-demented controls, we investigated global disruptions in the co-regulation of genes in two neurodegenerative diseases, late-onset Alzheimer's disease (AD) and Huntington's disease (HD). We identified networks of differentially co-expressed (DC) gene pairs that either gained or lost correlation in disease cases relative to the control group, with the former dominant for both AD and HD and both patterns replicating in independent human cohorts of AD and aging. When aligning networks of DC patterns and physical interactions, we identified a 242-gene subnetwork enriched for independent AD/HD signatures. This subnetwork revealed a surprising dichotomy of gained/lost correlations among two inter-connected processes, chromatin organization and neural differentiation, and included DNA methyltransferases, DNMT1 and DNMT3A, of which we predicted the former but not latter as a key regulator. To validate the inter-connection of these two processes and our key regulator prediction, we generated two brain-specific knockout (KO) mice and show that Dnmt1 KO signature significantly overlaps with the subnetwork (P = 3.1 × 10−12), while Dnmt3a KO signature does not (P = 0.017).Molecular Systems Biology 07/2014; 10(7). DOI:10.15252/msb.20145304 · 14.10 Impact Factor
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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 . 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 . Furthermore, the loss of orientation tuning accompanied a progressive deficit in a visual pattern discrimination task , which suggests that the neuronal dysfunction may lead to functional decline in visual processing. "
ABSTRACT: Alzheimer's disease (AD) is the most common form of age-related dementia, which is thought to result from overproduction and/or reduced clearance of amyloid-beta (A β ) peptides. Studies over the past few decades suggest that A β is produced in an activity-dependent manner and has physiological relevance to normal brain functions. Similarly, physiological functions for β - and γ -secretases, the two key enzymes that produce A β by sequentially processing the amyloid precursor protein (APP), have been discovered over recent years. In particular, activity-dependent production of A β has been suggested to play a role in homeostatic regulation of excitatory synaptic function. There is accumulating evidence that activity-dependent immediate early gene Arc is an activity "sensor," which acts upstream of A β production and triggers AMPA receptor endocytosis to homeostatically downregulate the strength of excitatory synaptic transmission. We previously reported that Arc is critical for sensory experience-dependent homeostatic reduction of excitatory synaptic transmission in the superficial layers of visual cortex. Here we demonstrate that mice lacking the major neuronal β -secretase, BACE1, exhibit a similar phenotype: stronger basal excitatory synaptic transmission and failure to adapt to changes in visual experience. Our results indicate that BACE1 plays an essential role in sensory experience-dependent homeostatic synaptic plasticity in the neocortex.Neural Plasticity 05/2014; 2014:128631. DOI:10.1155/2014/128631 · 3.60 Impact Factor
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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. "
ABSTRACT: Cell death and synapse dysfunction are two likely causes of cognitive decline in AD. As cells die and synapses lose their drive, remaining cells suffer an initial decrease in activity. Neuronal homeostatic synaptic scaling then provides a feedback mechanism to restore activity. This homeostatic mechanism is believed to sense levels of activity-dependent cytosolic calcium within the cell and to adjust neuronal firing activity by increasing the density of AMPA synapses at remaining synapses to achieve balance. The scaling mechanism increases the firing rates of remaining cells in the network to compensate for decreases in network activity. However, this effect can itself become a pathology, as it produces increased imbalance between excitatory and inhibitory circuits, leading to greater susceptibility to further cell loss via calcium-mediated excitotoxicity. Here, we present a mechanistic explanation of how directed brain stimulation might be expected to slow AD progression based on computational simulations in a 470-neuron biomimetic model of a neocortical column. The simulations demonstrate that the addition of low-intensity electrostimulation (neuroprosthesis) to a network undergoing AD-like cell death can raise global activity and break this homeostatic-excitotoxic cascade. The increase in activity within the remaining cells in the column results in lower scaling-driven AMPAR upregulation, reduced imbalances in excitatory and inhibitory circuits, and lower susceptibility to ongoing damage.Frontiers in Computational Neuroscience 04/2014; 8:39. DOI:10.3389/fncom.2014.00039 · 2.23 Impact Factor