Age-related changes in expression of ampa-selective glutamate receptor subunits: Is calcium-permeability altered in hippocampal neurons?

doi:10.1016/0306-4522(94)90422-7

Neuroscience

Volume 61, Issue 3, August 1994, Pages 429-433

https://doi.org/10.1016/0306-4522(94)90422-7 Get rights and content

Abstract

Age-related decline of cognition and memory, in humans and other animals, appears to be associated with neuronal loss.^6,9,28 Experimental and clinical evidence has shown that the hippocampal formation is one of the brain regions most vulnerable to the ageing process.^{1,2,10,11,13,17,18,20,23} Because excess of glutamate is neurotoxic to hippocampal neurons,³ abnormalities in glutamate neurotransmitter function may play a crucial role in neurodegenerative disorders, especially in conjunction with brain ageing.^8,14 We have usedin situ hybridization to study the expression of the two major α -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-selective glutamate receptor subunits, involved in the control of calcium permeability in the young adult and aged rat hippocampus. We show that the levels of messenger RNA encoding the AMPA-selective glutamate receptor subunit-1 (GluR1 or GluRA) and AMPA-selective glutamate receptor subunit-2 (GluR2 or GluRB) are highest in the dentate gyrus, followed by the CA1 and CA3 hippocampal subfields. We also show that the levels of both messenger RNAs decrease differentially with age in all subfields of the hippocampus. Finally, the GluR1/GluR2 messenger RNA ratios increase in the aged hippocampus, particularly in the CA3 subfield, suggesting that altered calcium homeostasis may contribute to age-related neuronal death.

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The levels of messenger RNA encoding the AMPA-selective glutamate receptor subunit-1, GluR1 and GluR2 are the highest in the dentate gyrus, followed by the CA1 and CA3 hippocampal subfields [77], suggesting that the dentate gyrus is susceptible for the influx of Ca2+ and Zn2+. The GluR1/GluR2 messenger RNA ratios, an index of calcium-permeable AMPA receptors, are increased in the aged hippocampus, suggesting that intracellular Zn2+ dyshomeostasis, in addition to intracellular Ca2+ dyshomeostasis, may contribute to age-related neuronal death in the hippocampus including the dentate gyrus [77], which may be linked to cognitive decline in elderly people (Fig. 1). The social behavioral deficits are accompanied by a change in AMPA receptor composition, which is regulated by the brain-enriched microRNA-124, leading to an imbalance between calcium-permeable and calcium-impermeable AMPA receptors [89].
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Furthermore, age-related changes in hippocampal synaptic plasticity have been shown to correlate with altered patterns of glutamate neurotransmission (Barnes, 1979; Barnes and McNaughton, 1980; Barnes et al., 2000; Gleichmann et al., 2011). Changes in expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit GluA1 associated with aging were suggested to lead to changes in synaptic plasticity (Kim et al., 2005) and may be associated with age-dependent cognitive impairment (Pagliusi et al., 1994). In addition, the implication of AMPAR current in age-related changes in memory formation was supported by the recovery of age-related cognitive decline in rats via treatment with an AMPAR modulator (Bloss et al., 2008).
Memory deficit is a common manifestation of age-related cognitive impairment, of which depression is a frequently occurring comorbidity. Previously, we developed a submissive (Sub) mouse line, validated as a model of depressive-like behavior. Using learning paradigms testing hippocampus-dependent spatial and nonspatial memory, we demonstrate here that Sub mice developed cognitive impairments at earlier age (3 months), compared with wild-type mice. Furthermore, acute hippocampal slices from Sub animals failed to display paired-pulse facilitation, whereas primed burst stimulation elicited significantly enhanced long-term potentiation in region CA1, relative to control mice. Changes in synaptic plasticity were accompanied by markedly reduced hippocampal messenger RNA expression of insulin-like growth factor and brain-derived neurotrophic factor. Finally, we identified markedly elevated protein levels of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 in the hippocampi of Sub mice, which was exacerbated with age. Taken together, the results point to a linkage between depressive-like behavior and the susceptibility to develop age-related cognitive impairment, potentially by hippocampal α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor–mediated glutamatergic signaling.
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Normal aging is associated with a significant decline in cognitive processes including executive functions and memory. Similar to humans, cognitive decline is highly variable in the aging population of monkeys and rodents and some aged individuals function as well as young adults. Thus identification of neurobiological features that underlie age-related cognitive decline has been the subject of intense investigation. The prefrontal cortex (PFC) has been extensively studied for its critical role in executive function while the hippocampus and related cortical regions have been the major targets of research for memory function. For many years, it was assumed that the decline in cognitive function with aging was a consequence of neuronal loss. However, more recent studies using unbiased stereological techniques have mostly failed to detect age-related neuronal loss in the PFC and hippocampus in the absence of neurodegenerative disease. Due to the lack of anatomical or neuronal number changes with aging, recent effort has focused on investigating the density, morphology, and molecular makeup of synapses and how they relate to aging and cognitive decline. Several of these studies have been carried out in behaviorally characterized young and aged monkeys. Recent evidence suggests that the critical synaptic subtypes associated with cognitive decline are different between the PFC and hippocampus and dependent on the types of cognitive function. In the PFC, the dendritic spine subtype most vulnerable to aging and coupled to task acquisition rate is the smallest of the thin spines. In the hippocampal dentate gyrus, synapse density and size remain stable with aging, but the density of large mushroom spines with perforated synapses correlates with recognition memory accuracy. In addition to these morphological findings, this chapter will also review age-related changes in ionotropic glutamate receptors and how they relate to cognitive function. Finally, the beneficial effects of estrogen on aging and cognitive decline are discussed in the context of potential morphological and molecular mechanisms.
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The calcium permeability of AMPA receptors is determined by the GluR2 subunit [43]. This subunit declines during ageing [51], potentially altering the cellular calcium dynamics. The altered calcium flux may contribute to the neurodegeneration associated with ageing [16].
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Age-related changes in expression of ampa-selective glutamate receptor subunits: Is calcium-permeability altered in hippocampal neurons?

Abstract

Neuron

Neurobiol. Aging

Brain Res.

Trends Neurosci.

Trends Neurosci.

Brain Res.

Brain Res.

Prog. Brain Res.

Trends pharmac. Sci.

Neurosci. Lett.

Trends Neurosci.

Neurobiol. Aging

Reactive Synaptogenesis in hippocampal area CA1 of aged and young adult rats

J. comp. Neurol.

The effects of aging on muscarinic receptor/G-coupling in the rat hippocampus and striatum

Brain Res.

In vitro autoradiography of hippocampal excitatory amino acid binding in aged Fischer 344 rats: relationship to performance on the water maze

Behav. Neurosci.

The early detection of brain pathology in Alzheimer's disease