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.

Alzheimer's disease (AD) is characterized by a progressive dysfunction of central neurons. Recent experimental evidence indicates that in the cortex, in addition to the silencing of a fraction of neurons, other neurons are hyperactive in amyloid-β (Aβ) plaqueenriched regions. However, it has remained unknown what comes first, neuronal silencing or hyperactivity, and what mechanisms might underlie the primary neuronal dysfunction. Here we examine the activity patterns of hippocampal CA1 neurons in a mouse model of AD in vivo using two-photon Ca 2+ imaging. We found that neuronal activity in the plaque-bearing CA1 region of older mice is profoundly altered. There was a marked increase in the fractions of both silent and hyperactive neurons, as previously also found in the cortex. Remarkably, in the hippocampus of young mice, we observed a selective increase in hyperactive neurons already before the formation of plaques, suggesting that soluble species of Aβ may underlie this impairment. Indeed, we found that acute treatment with the γ-secretase inhibitor LY-411575 reduces soluble Aβ levels and rescues the neuronal dysfunction. Furthermore, we demonstrate that direct application of soluble Aβ can induce neuronal hyperactivity in wild-type mice. Thus, our study identifies hippocampal hyperactivity as a very early functional impairment in AD transgenic mice and provides direct evidence that soluble Aβ is crucial for hippocampal hyperactivity.brain disease | in vivo imaging A lzheimer's disease (AD) is associated with multiple neuronal dysfunctions, including impairments underlying the storage and processing of information in the brain (1). One of the major functional defects in AD is a massive decrease in neuronal activity (2, 3). This generalized silencing of brain circuits generated the synaptic failure hypothesis (4). Interestingly, more recent studies revealed a more complex picture of the neuronal defects in AD, demonstrating a mix of both hypoactivity and hyperactivity in various brain regions. For example, in transgenic mice overexpressing both mutant human amyloid precursor protein (APP) and mutant human presenilin 1 (PS1), half of the neurons in layer 2/3 of the cortex were functionally impaired, with a decrease in neuronal activity in 29% of the neurons (termed "silent" neurons) and a profound increase in more than 20% of neurons (termed "hyperactive" neurons) (5). Interestingly, the increase in hyperactive neurons was most prominent in the vicinity of plaques. Such alterations of cortical activity were not observed in predepositing transgenic mice or in wild-type mice, indicating that the changes in neuronal activity were temporally correlated with the histological pathology. Consistently, resting Ca 2+ levels in cortical dendrites of APP/PS1 transgenic mice were substantially increased in the area surrounding plaques (6). Furthermore, APP transgenic mice exhibited nonconvulsive seizure activity in cortex and hippocampus, which was associated with GABAergic sprouting, enhanced synaptic inhibition, and syna...