Impaired spatial coding and neuronal hyperactivity in the medial entorhinal cortex of APP NL-G-F mice

Rodriguez, G. A.; Rothenberg, E. F.; Shetler, C. O.; Aoun, A.; Posani, L.; Vajram, S. V.; Tedesco, T.; Fusi, S.; Hussaini, S. A.

doi:10.1101/2024.11.26.624990

bioRxiv · 10.1101/2024.11.26.624990

Impaired spatial coding and neuronal hyperactivity in the medial entorhinal cortex of APP NL-G-F mice

Rodriguez, G. A.·Rothenberg, E. F.·Shetler, C. O.·Aoun, A.·Posani, L.·Vajram, S. V.·Tedesco, T.·Fusi, S.·Hussaini, S. A.

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Abstract

The progressive accumulation of amyloid beta (A{beta}) pathology in the brain has been associated with aberrant neuronal network activity and poor cognitive performance in preclinical mouse models of Alzheimers disease (AD). Presently, our understanding of the mechanisms driving pathology-associated neuronal dysfunction and impaired information processing in the brain remains incomplete. Here, we assessed the impact of advanced A{beta} pathology on spatial information processing in the medial entorhinal cortex (MEC) of 18-month App NL-G-F/NL- G-F knock-in (APP KI) mice as they explored contextually novel and familiar open field arenas in a two-day, four-session recording paradigm. We tracked single unit firing activity across all sessions and found that spatial information scores were decreased in MEC neurons from APP KI mice versus those in age-matched C57BL/6J controls. MEC single unit spatial representations were also impacted in APP KI mice. Border cell firing preferences were unstable across sessions and spatial periodicity in putative grid cells was disrupted. In contrast, MEC border cells and grid cells in Control mice were intact and stable across sessions. We then quantified the stability of MEC spatial maps across sessions by utilizing a metric based on the Earth Movers Distance (EMD). We found evidence for increased instability in spatially-tuned APP KI MEC neurons versus Controls when mice were re-exposed to familiar environments and exposed to a novel environment. Additionally, spatial decoding analysis of MEC single units revealed deficits in position and speed coding in APP KI mice in all session comparisons. Finally, MEC single unit analysis revealed a mild hyperactive phenotype in APP KI mice that appeared to be driven by narrow-spiking units (putative interneurons). These findings tie A{beta}-associated dysregulation in neuronal firing to disruptions in spatial information processing that may underlie certain cognitive deficits associated with AD.

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Rodriguez, G. A., Rothenberg, E. F., Shetler, C. O., Aoun, A., Posani, L., Vajram, S. V., Tedesco, T., Fusi, S., Hussaini, S. A.. 2024-11-26. Impaired spatial coding and neuronal hyperactivity in the medial entorhinal cortex of APP NL-G-F mice. https://doi.org/10.1101/2024.11.26.624990

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