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Summary: There is a growing consensus that Alzheimer's disease (AD) involves failure of the homeostatic machinery, which underlies the firing stability of neural circuits. What are the culprits leading to neuron firing instability? The amyloid precursor protein (APP) is central to AD pathogenesis, and we recently showed that its intracellular domain (AICD) could modify synaptic signal integration. We now hypothesize that AICD modifies neuron firing activity, thus contributing to the disruption of memory processes. Using cellular, electrophysiological, and behavioral techniques, we show that pathological AICD levels weaken CA1 neuron firing activity through a gene-transcription-dependent mechanism. Furthermore, increased AICD production in hippocampal neurons modifies oscillatory activity, specifically in the γ-frequency range, and disrupts spatial memory task. Collectively, our data suggest that AICD pathological levels, observed in AD mouse models and in human patients, might contribute to progressive neuron homeostatic failure, driving the shift from normal aging to AD. : Pousinha et al. report that increased AICD levels, a peptide representing amyloid precursor protein (APP) C-terminal domain, render CA1 pyramidal neurons hypoexcitable by altering Ca+ and K+ channel conductances. Modeling this alteration predicts decreased gamma oscillations. They show that increasing AICD levels in vivo weakens gamma-oscillation-dependent spatial memory. Keywords: AICD, APP, Alzheimer’s disease, neuron firing, brain oscillations, memory encoding |
