2025 American Academy of Neurology Abstract Website

Objective:

We compared markers of neuronal activity elicited during spatial working memory in the 5xFAD amyloidosis model versus WT mice across subpopulations of dorsal hippocampal CA1 defined by neuronal location along the radial (superficial, deep) and transverse (CA1a, CA1c) axes.

Background:

Pyramidal neurons of CA1 are impacted early in Alzheimer disease (AD) to affect memory. The circuit basis of this memory deficit is unclear. Prior research suggests that CA1 contains genetically and functionally heterogeneous pyramidal neuron populations. For example, location-dependent activity becomes increasingly robust from CA1a (near subiculum) to CA1c (near CA2), and in deep (dPN) versus superficial (sPN) pyramidal neurons. We hypothesized that activity changes due to amyloidosis would also vary across these subpopulations.

Design/Methods:

A cohort of 5xFAD and WT mice (n = 8-10 female/group, 6-10 mo old) underwent the Y-maze spatial working memory assay. After behavior, immunohistochemical strategies were applied to quantify neuronal c-Fos expression, a marker of neuronal activity, in CA1 across radial and transverse axes. The c-Fos counts were normalized by the number of neurons per subpopulation observed by DAPI stain.

Results:

Compared to WT, in 5xFAD mice there was a 30% reduction in the activity of CA1a (p = 0.0084) and CA1c dPN’s (p = 0.0004). There were no other statistically significant activity reduction across genotype in the other CA1 subpopulations.

Conclusions:

Spatial working memory deficits in 5xFAD mice arise from dysfunction of the dPN subpopulation. This promotes further work on elucidating how amyloid impacts memory in a cell type-specific manner.