Weak-hyperactive hippocampal CA1 neurons in the prodromal stage of Alzheimer's disease in hybrid AppNL-G-F/NL-G-F × Thy1-GCaMP6s+/− mice suggest disrupted plasticity

Abstract

This study investigated the impact of familial Alzheimer's disease (AD)-linked amyloid precursor protein (App) mutations on hippocampal CA1 neuronal activity and function at an early disease stage in AppNL-G-F/NL-G-F × Thy1-GCaMP6s+/− (A-TG) mice using calcium imaging. Longitudinal assessment of spatial behavior at 12 and 18 months of age identified an early disease stage at 12 months when there was significant amyloid beta pathology with mild behavioral deficits. Hippocampal CA1 neuronal activity and event-related encoding of distance and time were therefore assessed at 12 months of age in several configurations of an air-induced running task to assess the dynamics of cellular activity. Neurons in A-TG mice displayed diminished (weaker) and more frequent (hyperactive) neuronal firing that was more pronounced during movement compared to immobility. Responsive neurons showed configuration-specific deficits in distance and time encoding with impairment in adapting their responses to changing configurations. These results suggest that at an early stage of AD in the absence of full-blown behavioral deficits, weak-hyperactive neuronal activity may induce impairments in sensory perception of changing environments.