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

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.

Positive Association Between Limbic Metabotropic Glutamate Receptor 5 Availability and Novelty-Seeking Temperament in Humans: An 18F-FPEB PET Study

“…Here, we found a negative association between mGluR5 availability and age in most brain regions, supporting the proposed involvement of this receptor in normal aging (29). This contrasts with the absence of age dependency recently reported using 11 C-ABP688, another mGluR5 tracer (31).…”

“…TCI scores were transformed to z scores based on the reference sample (n 5 1,034). Because mGluR5 is suggested to be involved in normal aging (29) and influenced by estrogen signaling (30), age and sex were included as nuisance variables in all analyses. PET data were primarily analyzed on a voxel-by-voxel basis using SPM12 (http://www.fil.ion.ucl.ac.uk/spm/software/spm12/).…”

Homer-1a immediate early gene expression correlates with better cognitive performance in aging

“…In contrast, mice overexpressing Homer-1a selectively and inducibly in striatal medium spiny neurons showed deficits in motor learning and performance as well as drug-induced stereotypy (Tappe and Kuner 2006). A recent study investigated the expression levels of Homer proteins in the hippocampus during aging in Long-Evans rats (Menard and Quirion 2012). However, while this study aimed at measuring the effect of behavioral training on immediate early gene expression, our present study aimed at investigating non-induced expression levels of members of the Homer-1 protein family.…”

“…For instance, coupling of inositol-1,4,5-trisphosphate receptors in the membranes of the endoplasmic reticulum and metabotropic glutamate receptors at the plasma membrane generates a structural and functional signaling domain (Tu et al 1998;Mao et al 2005;Menard and Quirion 2012) (Fig. 4).…”

Possible Role of Dynorphins in Alzheimer's Disease and Age-Related Cognitive Deficits

“…Protein concentration was determined using the bicinchoninic acid protein assay kit (Pierce, Rockford, Ill., USA). Western blot analysis was carried out on homogenates as described previously [17] with primary antibodies against GluR1, GluR2, NR2A, NR2B (dilution 1:1,000; Abcam, Cambridge, Mass., USA) and NR1 (dilution 1:2,000; Santa Cruz Biotechnology, Santa Cruz, Calif., USA). The actin level was used as a loading control, and 20 µg of proteins were loaded since this protein concentration was revealed as optimal for all the antibodies by serial dilutions of young WT reference samples (0, 3.125, 6.25, 12.5, 25, 50 and 100 µg; data not shown), done according to Halim et al [18].…”