Abstract
Normal aging is generally characterized by a slow decline of cognitive abilities albeit with marked individual differences. Several animal models have been studied to explore the molecular and cellular mechanisms underlying this phenomenon. The excitatory neurotransmitter glutamate and its receptors have been closely linked to spatial learning and hippocampus-dependent memory processes. For decades, ionotropic glutamate receptors have been known to play a critical role in synaptic plasticity, a form of adaptation regulating memory formation. Over the past 10 years, several groups have shown the importance of group 1 metabotropic glutamate receptor (mGluR) in successful cognitive aging. These G-protein-coupled receptors are enriched in the hippocampal formation and interact physically with other proteins in the membrane including glutamate ionotropic receptors. Synaptic plasticity is crucial to maintain cognitive abilities and long-term depression (LTD) induced by group 1 mGluR activation, which has been linked to memory in the aging brain. The translation and synthesis of proteins by mGluR-LTD modulate ionotropic receptor trafficking and expression of immediate early genes related to cognition. Fragile X syndrome, a genetic form of autism characterized by memory deficits, has been associated to mGluR receptor malfunction and aberrant activation of its downstream signaling pathways. Dysfunction of mGluR could also be involved in neurodegenerative disorders like Alzheimer’s disease (AD). Indeed, beta-amyloid, the main component of insoluble senile plaques and one of the hallmarks of AD, occludes mGluR-dependent LTD leading to diminished functional synapses. This review highlights recent findings regarding mGluR signaling, related synaptic plasticity, and their potential involvement in normal aging and neurological disorders.
Highlights
Normal aging is generally characterized by a slow decline of cognitive abilities albeit with marked individual differences
Behavioral studies of rodent animal models are useful to explore mechanisms underlying memory deficits associated to aging
The inhibition of mammalian target of rapamycin (mTOR) prevents metabotropic glutamate receptor (mGluR)-long-term depression (LTD) induced by DHPG (Hou and Klann, 2004) and our group has recently shown a strong positive correlation between successful cognitive aging in LongEvans rats and downstream signaling pathways of group 1 mGluR activation including the mTOR cascade (Menard and Quirion, 2012)
Summary
Normal aging is generally characterized by a slow decline of cognitive abilities albeit with marked individual differences. We reported an increase in mGluR5 protein levels in the PSD of aged memory-unimpaired Long-Evans rats and inhibitory learning was highly conserved in this group in comparison with old memory-impaired animals (Menard and Quirion, 2012). Novel object recognition involves perirhinal cortex but we speculate that the confusion between old versus new platform positions reported for aged memory-impaired Long-Evans rats in the hippocampus-dependent MWM task could be explained by alterations in synaptic processes modulated by mGluR.
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