Modeling investigation of the amyloid precursor protein C-terminal domain effects on mouse CA1 pyramidal neurons

Neuronal excitability and ion channel dynamics are increasingly recognized as key markers of Alzheimer’s disease (AD) progression, alongside well-established synaptic dysfunction. Recent evidence implicates the amyloid precursor protein intracellular domain (AICD) in modulating both intrinsic excitability and synaptic properties of hippocampal pyramidal neurons. To investigate these effects, we analyzed in vitro recordings from hippocampal slices exposed to physiologically relevant AICD concentrations, revealing significant alterations in single-neuron electrophysiological properties. To dissect the underlying mechanisms and their implications for AD-related circuit dysfunction, we developed two complementary computational modeling frameworks. First, biophysically detailed, morphologically accurate, NEURON cellular models incorporating realistic ion channel distributions revealed that AICD exposure selectively perturbs key conductances — including Na+, KM, and KCa channels — resulting in altered firing frequency adaptation and excitability profiles. These models captured both passive and active membrane dynamics and provided mechanistic insight into AICD-induced shifts in input-output behavior. Second, we implemented Adaptive Generalized Leaky Integrate-and-Fire (A-GLIF) models optimized against experimental data, which reproduced subthreshold voltage trajectories and spike timing with high accuracy. Critically, these reduced models will enable the generation of full-scale CA1 network models reflecting the heterogeneity observed in both control and AICD-treated cells. The A-GLIF framework further supports scalable network simulations, paving the way for circuit-level exploration of AICD-related dysfunction. These findings demonstrate that physiologically relevant levels of AICD are sufficient to drive measurable shifts in neuronal excitability, with clear implications for disease progression and therapeutic targeting. Furthermore, the multiscale modeling approach bridges cellular-level electrophysiological alterations with network-level computational feasibility, establishing a powerful framework to quantify and simulate AICD-related pathophysiology in AD.