Proceedings of The Physiological Society

Experimental Models (Exeter, UK) (2018) Proc Physiol Soc 40, C03

Oral Communications

Spatial coding deficits in mouse models of dementia

T. Ridler1, K. G. Phillips2, A. Randall1, J. T. Brown1

1. Medical School, University of Exeter, Exeter, Devon, United Kingdom. 2. Eli Lilly UK, Surrey, Windlesham, United Kingdom.

Dementias are associated with severe spatial memory deficits which likely arises due to dysfunction in hippocampal and parahippocampal circuits. These circuits rely on precise encoding of directional and velocity information for spatially-sensitive neurons, such as grid cells in the medial entorhinal cortex (mEC), to faithfully represent the environment. In recent years, rodent models in particular have allowed for the detailed understanding of this ‘internal GPS'. In this study, high density silicon probe electrode arrays were stereotaxically implanted to examine the firing rate coding properties of mEC neurons in male rTg4510 mice (7-8 month old), a mouse model of tauopathy which displays severe spatial memory deficits. Animals were anaesthetised using isoflurane (4%) and maintained at 1-2% during surgery. After recovery, single-unit activity was recorded while animals explored either a linear track or open field. Speed, head direction and spatial firing scores were calculated for each cell and compared to a distribution of scores produced from shuffled data. Cells were classified as significant if their score was greater than the 95th percentile of the shuffled distribution. Grid cell firing patterns were largely absent in rTg4510 mice (fig. 1), suggesting some, or all, of the information required for neural path integration is deficient (WT: 36/150, rTg4510: 3/129, χ2 (1) =18.63 p <0.0001, Chi-Square test). Interestingly, we found that head direction cells, a key component of any path integration system, are largely functionally intact (WT: 19/150, rTg4510: 12/129, χ2 (1) =0.79 p=0.37, Chi-Square test). In contrast, neural representation of running speed information was significantly disturbed in a number of ways. Firstly, a significantly smaller proportion of mEC cells recorded from rTg4510 mice had firing rates correlated with running speed, when compared to the 95th centile of a shuffled distribution of data produced from 250 shuffles for each cell (WT: 96/150, rTg4510: 17/129 χ2 (1) =74.3 p <0.05, Chi-Square test). Secondly, of those cells which are modulated by running speed a much greater proportion are negatively modulated (WT: 11/96, rTg4510: 6/17, χ2 (1) =6.42, p =0.011, Chi-Square test). Finally, the power of local field potential oscillations in the theta and gamma frequency bands, which in wildtype mice are tightly linked to running speed, was shown to be invariant in rTg4510 mice, with increased locomotor activity having little effect on oscillatory properties (linear regression; WT: R2=0.75, p<0.001, n=3, rTg4510: R2=0.15, p=0.03, n=5). Our results using rodent models reveal deficits in locomotor speed encoding that are likely to severely impact the ability of animals to continuously update positional information and thus disrupt path integration systems in these mice and in dementia patients.

Where applicable, experiments conform with Society ethical requirements