Successful Cognitive Aging in Rats: A Role for mGluR5 Glutamate Receptors, Homer 1 Proteins and Downstream Signaling Pathways

Caroline Ménard,Rémi Quirion,Mark P Mattson

doi:10.1371/journal.pone.0028666

Caroline Ménard, Rémi Quirion + Show 1 more

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https://doi.org/10.1371/journal.pone.0028666

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Abstract

Normal aging is associated with impairments in cognition, especially learning and memory. However, major individual differences are known to exist. Using the classical Morris Water Maze (MWM) task, we discriminated a population of 24-months old Long Evans aged rats in two groups - memory-impaired (AI) and memory-unimpaired (AU) in comparison with 6-months old adult animals. AI rats presented deficits in learning, reverse memory and retention. At the molecular level, an increase in metabotropic glutamate receptors 5 (mGluR5) was observed in post-synaptic densities (PSD) in the hippocampus of AU rats after training. Scaffolding Homer 1b/c proteins binding to group 1 mGluR facilitate coupling with its signaling effectors while Homer 1a reduces it. Both Homer 1a and 1b/c levels were up-regulated in the hippocampus PSD of AU animals following MWM task. Using immunohistochemistry we further demonstrated that mGluR5 as well as Homer 1b/c stainings were enhanced in the CA1 hippocampus sub-field of AU animals. In fact mGluR5 and Homer 1 isoforms were more abundant and co-localized in the hippocampal dendrites in AU rats. However, the ratio of Homer 1a/Homer 1b/c bound to mGluR5 in the PSD was four times lower for AU animals compared to AI rats. Consequently, AU animals presented higher PKCγ, ERK, p70S6K, mTOR and CREB activation. Finally the expression of immediate early gene Arc/Arg3.1 was shown to be higher in AU rats in accordance with its role in spatial memory consolidation. On the basis of these results, a model of successful cognitive aging with a critical role for mGluR5, Homer 1 proteins and downstream signalling pathways is proposed here.

Highlights

Aging is a natural process characterized by various physical alterations: slower reaction time, cognitive alterations and modification of the muscles density [1]
To further investigate the cellular mechanisms involved in successful cognitive aging, we studied metabotropic glutamate receptors (mGluR) levels and related signaling pathways in AI versus aged memory-unimpaired (AU) animals focusing on the hippocampal formation as a key structure involved in spatial learning [22]
We report for the first time an involvement of metabotropic glutamate receptors 5 (mGluR5) receptors, Homer 1 proteins, and their downstream signaling pathways in hippocampus-dependent spatial memory for successful cognitive aging

Summary

Introduction

Aging is a natural process characterized by various physical alterations: slower reaction time, cognitive alterations and modification of the muscles density [1]. We explored variability in cognitive abilities associated with normal aging using Long Evans rats as model. Alterations in gene expression have been proposed to at least partly explain this phenomenon [6,7]. Another hypothesis relates to the incapacity of AI subjects to adapt and properly encode new information [8]. Hippocampus-dependent spatial memory is not the only behavioural profile associated to Long Evans AI and AU sub-groups. A reduced reactivity to novelty in exploratory paradigms, gustatory/olfactory stimulus and an increased reaction to pain has been reported in AI animals whereas in AU animals all these behaviours were similar to young rats [3]

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