Abstract

The medial entorhinal cortex (MEC) harbors diverse spatially and object-tuned cell types essential for spatial coding and episodic memory, and is among the earliest regions affected in neurodegenerative diseases. Here, we examined how early neurodegeneration alters MEC cellular coding, network dynamics, and behavior in two Alzheimer mouse models of distinct etiology. Specifically, we performed in vivo electrophysiology, immunohistochemistry and behavioral assays in models that reflect the manifestation of a tauopathy and amyloidopathy, respectively, to identify common impairments. In both models, the earliest deficits manifested as instability of spatial context representations at the cellular and behavioral level. These impairments preceded model-specific disruptions in grid cell coding and altered theta oscillations. We further identified reduced parvalbumin-positive (PV+) septal projections as a likely contributor to MEC dysfunction. In contrast, object-vector coding remained intact, highlighting spatial context instability as an early marker of MEC impairment. ### Competing Interest Statement The authors have declared no competing interest. Deutsche Forschungsgemeinschaft, https://ror.org/018mejw64, SFB-1436/2 Project-ID 425899996, SFB/TRR384 IN-CODE, Advanced ERC grant Project-ID 101142587, NRRP grant, project MNESYS/PE0000006/DN.1553 11.10.2022 Manfred Lautenschläger-Stiftung