Regional changes in the hippocampal density of AMPA and NMDA receptors across the lifespan of the rat

doi:10.1016/S0006-8993(00)02792-X

Brain Research

Volume 885, Issue 1, 1 December 2000, Pages 1-5

https://doi.org/10.1016/S0006-8993(00)02792-X Get rights and content

Abstract

The current study dissected the fascia dentata (FD) and hilar region from the CA and subicular cell fields of the rat and conducted in vitro determinations of the number of binding sites for N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) glutamate receptors across the lifespan. We determined the density of binding of [³H]-glutamate or [³H]-AMPA to NMDA or AMPA receptor sites, respectively. The changes reported might be due to either a change in receptor number or an alteration in the binding characteristics of the receptor site with aging. We found an age-related decline in the number of NMDA receptors in the CA1, CA3 and subicular cell regions of the hippocampus, but not in the FD/hilar region, and an age-related decline in the number of AMPA receptors in the FD/hilar region, but not in the CA fields. The decline in the number of NMDA or AMPA receptors that occurs with aging was not a continuous or homogeneous process. These changes in receptor number might underlie selected age-associated changes in sensitivity to drugs that influence hippocampal function as well as to changes in NMDA-dependent long-term potentiation. A thorough understanding of the mechanisms underlying changes in glutamate receptor function in discrete brain regions, using combined neurochemical and electrophysiological methods, may ultimately provide insight into the fundamental substrates of age-associated memory disorders related to hippocampal dysfunction.

Introduction

Normal aging is associated with a decline in hippocampal-dependent mnemonic abilities in humans [1], non-human primates [2] and rodents [4]. Glutamate is an important neurotransmitter at hippocampal synapses and is known to be critical for normal learning and memory processes [8]. Glutamate receptors that are sensitive to either N-methyl-d-aspartate (NMDA) or α-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) are involved in synaptic modification that can be induced in this structure [7], [8] that has been hypothesized to reflect a mechanism of information storage [6], [16]. Pharmacological blockade of these glutamate receptor subtypes impairs learning and memory performance [17] and can block the induction of long-term potentiation (LTP) in the hippocampus [19]. While facilitation of the function of these receptor subtypes can enhance memory [24], hyperactivity of these neurotransmitter receptors may underlie the neurodegenerative changes and decline in hippocampal function associated with aging [20]. Investigations of changes in the number of these receptors in aging populations have produced conflicting results. Laboratories have reported either no change [23] or a decline [7], [15], [21], [25], [26] in numbers of these receptors within the hippocampus. Much of this variation may be related to differences in the species or strain investigated [13], [15] or the particular ligand used in the binding assays. In addition, the apparent discrepancy might also be related to regional changes in receptor density within the hippocampus. In the present study, we dissected the fascia dentata (FD), and hilar region from the CA and subicular cell fields and conducted in vitro determinations of the number of binding sites for AMPA and NMDA glutamate receptors across the lifespan.

Section snippets

Subjects

Thirty-eight male Sprague–Dawley rats (National Institute on Aging, Bethesda, MD) were fed ad libitum and housed under 12/12 h light conditions until sacrificed. The age (in months) and number (in parentheses) of rats used in this study were as follows: 3 (3), 6(3), 9(3), 12(2), 14(1), 15(2), 16(1), 17(1), 18(2), 23(2), 24(2), 25(4), 26(2), 28(2), 29(7) and 31(1).

Tissue dissection

The rats were briefly anesthetized using metophane gas and then quickly sacrificed by decapitation. The brains were quickly removed

NMDA receptor changes

There was a significant main effect of Age [F_11,34=2.89, P=0.0016] for the number of NMDA receptors in the CA region of the hippocampus. Post-hoc comparisons using Student–Newman–Keuls method found that levels of NMDA receptors in the 25 and 29 month groups differed significantly (P<0.05) from the 3 month levels. In contrast, there was no significant main effect of Age [F_11,34=1.14, P=0.38] for the number of NMDA receptors in the FD region. The results are shown in the top frame of Fig. 2: the

Discussion

The current investigation provides a converging line of evidence with earlier autoradiographic studies of age-related changes in hippocampal glutamatergic receptors [7], [13], [15] and extends these findings across a wider range of ages. The main findings of this study are that there is an age-related decline in the number of NMDA receptors in the CA1, CA3 and subicular cell regions of the hippocampus, but not in the FD/hilar region, and an age-related decline in the number of AMPA receptors in

Acknowledgements

Supported by the U.S. Public Health Service, Contract grant number AG10546 and an Alzheimer’s Association, IIRG-95-004 award to GLW and AG03376 to CAB. We thank Bruce McNaughton for developing the microdissection procedure used in these experiments, and Geeta Rao and Frank Houston for assistance with the dissections.

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Research reportRegional changes in the hippocampal density of AMPA and NMDA receptors across the lifespan of the rat

Abstract

Introduction

Section snippets

Subjects

Tissue dissection

NMDA receptor changes

Discussion

Acknowledgements

Neurobiol. Aging

Neurobiol. Aging

Neurobiol. Aging

Neurobiol. Aging

Neurobiol. Aging

Brain Res.

Mech. Aging Dev.

Neurobiol. Aging

Pharmacol. Biochem. Behav.

Prog. Neurobiol.

Neurosci.

Neurobiol. Aging

Brain Res.

Research report
Regional changes in the hippocampal density of AMPA and NMDA receptors across the lifespan of the rat