Clusters of Hyperactive Neurons Near Amyloid Plaques in a Mouse Model of Alzheimer's Disease

TLDR

The neurodegeneration seen in Alzheimer’s disease is linked to synaptic dismantling and a progressive decline in neuronal activity. The study aimed to test whether neuronal activity decreases in Alzheimer’s disease in vivo. Two‑photon Ca²⁺ imaging was employed in a mouse model of Alzheimer’s disease to assess neuronal activity. Although 29 % of layer 2/3 cortical neurons showed reduced activity, 21 % were hyperactive near amyloid plaques, likely due to diminished synaptic inhibition, indicating that a redistribution of synaptic drive, rather than a global loss of activity, contributes to cortical dysfunction in 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.