Spatial coding defects of hippocampal neural ensemble calcium activities in the 3xTg-AD Alzheimer’s disease mouse model

Abstract

Background Alzheimer’s disease (AD) causes progressive age-related defects in memory and cognitive function, and has emerged as a major health and socio-economic concern in the US and worldwide. To develop effective therapeutic treatments for AD, we need to better understand the neural mechanisms by which AD causes memory loss and cognitive deficits. Methods Here we examine large scale hippocampal neural population calcium activities imaged at single cell resolution in a triple-transgenic Alzheimer’s disease mouse model (3xTg-AD) that presents both amyloid plaque and neurofibrillary pathological features along with age-related behavioral defects. To measure encoding of environmental location in hippocampal neural ensembles in the 3xTg-AD mice in vivo, we performed GCaMP6-based calcium imaging using head-mounted, miniature fluorescent microscopes (“miniscopes”) on freely moving animals. We compared hippocampal CA1 excitatory neural ensemble activities during open-field exploration and track-based route-running behaviors in age-matched AD and control mice at young (3–6.5 months old) and old (18–21 months old) animals. Results 3xTg-AD CA1 excitatory cells display significantly higher calcium activity rates compared with Non-Tg controls for both the young and old age groups during spatial exploration, suggesting that in vivo enhanced neuronal calcium ensemble activity is a disease feature. Increased ages are correlated with decreased neural calcium activity rates across genotypes. CA1 neuronal populations of 3xTg-AD mice show lower spatial information scores compared with control mice. Spatial firing of CA1 neurons of old 3xTg-AD mice also displays higher sparsity and spatial coherence, indicating less place specificity for spatial representation. We find locomotion significantly modulates the amplitude of hippocampal neural calcium ensemble activities in 3xTg-AD mice, but not in non-transgenic controls during open field ambulatory movements. Conclusions Our data offers new and comprehensive information about age-dependent neural circuit activity changes in this important AD mouse model, and provides strong evidence that spatial coding defects in the neuronal population activities are associated with AD pathology and AD-related memory behavioral deficits.