Group 1 Metabotropic Glutamate Receptor Function and Its Regulation of Learning and Memory in the Aging Brain

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.

Glutamate presynaptic vesicular transporter and postsynaptic receptor levels correlate with spatial memory status in aging rat models

“…Group I mGluR-mediated plasticity has also been associated with successful cognitive aging in rats (Menard and Quirion, 2012a;Yang et al, 2013), and these receptors have been implicated in learning and memory, AD, autism, and mental retardation (Luscher and Huber, 2010). Like NMDA NR2 receptor subunits, mGluR1a and mGluR5 postsynaptic levels were positively correlated with old rodents' MWM performances.…”

“…The LE rat has been extensively used for aging studies. Interestingly, a subgroup of older LE animals maintains high cognitive abilities despite aging, whereas another one shows impairments which is similar to individual differences observed in humans (Menard and Quirion, 2012a). The LOU rat strain is considered a model of successful aging, as it is characterized by increased lifespan, maintenance of a low and stable adipose tissue mass throughout life, and low incidence of age-related diseases (Alliot et al, 2002).…”

The olfactory bulbectomized rat as a model of depression: The hippocampal pathway

“…However, the aforementioned tasks are not often used to evaluate memory-related tasks in rodents and therefore have limited value. Rather, in the Morris Water Maze (MWM), one of the most common tools used to evaluate hippocampal-related learning and memory [107,108], OBX animals exhibit a delay in spatial memory acquisition as early as day two of training [25,109,110]-suggesting a delay in spatial memory acquisition.…”

Molecular and cellular aspects of age-related cognitive decline and Alzheimer’s disease

“…This includes mGluR-dependent and voltage-dependent calcium channel (VDCC)-dependent LTP [51,101,104]. Successful cognitive aging has also been correlated with a transition to mGluR-dependent LTD [103,105].…”