Early developmental abnormalities in hippocampal synapse distribution in a mouse model of Alzheimer’s disease Development of new models and analysis methods/novel assays and technologies

• Published in: Alzheimer's & dementia Vol. 16; no. S2
• Main Authors: Ray, Ajit, Bernhard, Sarah M., Kuljis, Dika A., Bruchez, Marcel P., Barth, Alison L
• Format: Journal Article
• Language: English
• Published: 01.12.2020
• ISSN: 1552-5260; 1552-5279
• DOI: 10.1002/alz.044118

Abstract Background Alzheimer’s disease (AD) has long been described as a disease arising from progressive loss of synapses and cell death. While this is certainly true for the late stages of AD when patient present with clinical symptoms, it has increasingly become a focus of research that early AD may be paradoxically characterized by hyperexcitability and hyperactivity of neurons, specifically in hippocampal CA1 pyramidal neurons. In this study using a transgenic animal model of AD, we investigated whether an alteration in input‐specific synapse numbers could explain this early hyperactivity. Method B6C3‐Tg(APPswe,PSEN1dE9) mice (APP/PS1) and wild‐type littermates of different ages and both sexes were injected with our novel pan‐synaptic labeling reagent (AAV1‐FAPpost) (Kuljis et al, 2019) in the dorsal hippocampal CA1 region. Labeled pyramidal cells were reconstructed and quantitative synaptic analysis across dendritic compartments was performed. Result Even at postnatal day 21, CA1 pyramidal neurons from mutant mice showed an increase in the number of medial apical synapses (site for CA3 inputs) and a decrease in distal apical tuft synapses (site for entorhinal inputs), that may persist through adulthood. Proximal apical and basal synapses remained unaffected. Similar analysis in aged transgenic animals (13‐14 months) showed a uniform loss of synapses across all compartments. Conclusion The compartment‐specific increase in CA3 to CA1 synapses during early development suggests that APP/amyloid‐β may be associated with abnormal synapse formation or stabilization. This increase in excitatory connectivity is consistent with hippocampal hyperexcitability that has been described in preclinical AD. This aberrant increase in CA3 may arise to compensate for the loss of entorhinal inputs and delay the onset of behavioral deficits. Our study demonstrates how AD pathology may progressively damage neural circuit function by inducing primary synaptic deficits and aberrant compensatory reweighting of other synaptic connections.