The role of afferent hippocampal to prefrontal cortex projections in a mouse model of Alzheimer's disease

Alzheimer’s disease (AD) is characterized by memory deficits including spatial working memory. The hippocampus (HPC) and the prefrontal cortex (PFC) exhibit a prominent AD pathology and are relevant brain regions for spatial working memory. The HPC and PFC are connected by long-range projections and operate in synergy to consolidate and retrieve memories. Both, excitatory and inhibitory long-range projections between the HPC and the PFC have been poorly characterized under AD-like conditions. In fact, it remains unknown, whether structural and functional connectivity deficits between these brain areas are causally linked to spatial working memory deficits under AD-like conditions.To investigate this, we utilized APP/PS1dE9 transgenic mice, a mouse model for amyloidosis that recapitulates important aspects of AD. We used a Cre-driver mouse line to target gabaergic interneurons by AAV-mediated Cre-dependent fluorophore and chemogenetic tool expression to conduct neuronal tracings and manipulate neuronal activity, respectively. Moreover, we performed in vivo three-photon Ca2+-imaging in the PFC of awake, head-fixed mice to functionally characterize PFC inputs.Our data show the accumulation of amyloid-β plaques in the PFC. Furthermore, we observed a novel monosynaptic gabaergic axonal projection originating in the ventral HPC and targeting the PFC. These projections showed amyloid pathology-associated structural alterations and a decreased density. These results indicate that structural and potentially functional connectivity impairments between HPC and PFC might underlie spatial working memory deficits in a mouse model with AD-like pathology.