Impairments in experience-dependent scaling and stability of hippocampal place fields limit spatial learning in a mouse model of Alzheimer's disease

Abstract

Impaired spatial memory characterizes many mouse models for Alzheimer's disease, but we understand little about how this trait arises. Here we use a transgenic model of amyloidosis to examine the relationship between behavioral performance in tests of spatial navigation and the function of hippocampal place cells. We find that APP mice require considerably more training than controls to reach the same level of performance in a water maze task, and recall the trained location less well 24 hours later. At a single cell level, place fields from control mice become more stable and spatially restricted with repeated exposure to a new environment, while those in APP mice improve less over time, ultimately producing a spatial code of lower resolution, accuracy, and reliability than controls. The limited refinement of place fields in APP mice likely contributes to their delayed water maze acquisition, and provides evidence for circuit dysfunction underlying cognitive impairment.

Impairments in spatial representations and rhythmic coordination of place cells in the 3xTg mouse model of Alzheimer's disease

“…Decreased stability was observed for both place field locations and firing rates. These results are consistent with prior studies that tested place field stability over consecutive laps (Cheng and Ji, ; Ciupek et al, ; Booth et al, ) or sessions (Zhao et al, ) in other AD mouse models. In the latter study, the authors also used a Morris water maze (MWM) task to assess spatial memory at the behavioral level and found that APP Swe/Ind mice were deficient in spatial memory recall.…”

“…Here, we examined place cell representations of space and rhythmic coordination of place cells in the 3xTg mouse model of AD. These mice showed impairments in the stability of place cell maps and reductions in place cell firing rates that were consistent with a number of other rodent models of AD that overexpress disease-related tau and/or APP mutations (Cheng and Ji, 2013;Witton et al, 2014;Zhao et al, 2014;Ciupek et al, 2015;Booth et al, 2016). We also found that rhythmic coordination of place cell spiking by theta and slow gamma rhythms, but not fast gamma rhythms, was disrupted in freely behaving 3xTg mice.…”

“…Place cell abnormalities have been reported in several mouse models of AD (Cacucci et al, 2008;Cheng and Ji, 2013;Zhao et al, 2014;Cayzac et al, 2015;Booth et al, 2016). Moreover, disturbed theta and gamma oscillations in the hippocampus have been observed in transgenic and Ab injection models of AD (Villette et al, 2010;Rubio et al, 2012;Cheng and Ji, 2013;Ittner et al, 2014;Schneider et al, 2014;Cayzac et al, 2015;Ciupek et al, 2015;Gillespie et al, 2016;Iaccarino et al, 2016).…”

Disrupted‐in‐schizophrenia 1 overexpression disrupts hippocampal coding and oscillatory synchronization

“…Place cell goal‐coding deficits were reported in a mouse model where reduced DISC1 protein expression leads to a dopamine system disturbance, providing further evidence for dopaminergic involvement (Hayashi, Sawa, & Hikida, ). Interestingly, impaired space‐related place cell dynamics have also been observed in CMI models not based on DISC1 manipulations (Wolff & Bilkey, ; Zaremba et al, ) and amyloidosis‐based Alzheimer's disease models (Mably, Gereke, Jones, & Colgin, ; Zhao, Fowler, Chiang, Ji, & Jankowsky, ). Our study therefore supports previous CMI research involving place cell coding deficits.…”

Analysis for Science Librarians of the 2014 Nobel Prize in Physiology or Medicine: The Life and Work of John O’Keefe, Edvard Moser, and May-Britt Moser

“…An early indication of Alzheimer's is memory impairment, including the loss of spatial memory. A recent study by Zhao et al (2014) From the beginning of his scientific studies O'Keefe has been interested in the brain and behavior. He has focused his research on the limbic system and medial temporal lobe, specifically the amygdala and hippocampus.…”