Kathy R. Magnusson

Department of Anatomy & Neurobiology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523

Received 4/15/98 Accepted 4/20/98

2. INTRODUCTION

Aging causes functional declines in many organs of the body, including the brain. One of the earliest cognitive dysfunctions that humans experience is a decline in learning and memory performance. This deterioration is detectable already in the fifth decade of life (1). These declines in memory can range in severity from "benign senescent forgetfulness" (2), in which individuals have trouble accessing new and old information (3), to the degenerative disorder, Alzheimer's disease, which induces dementia and severe declines in cognitive functions (4). A better understanding of the underlying causes of these memory declines during aging is necessary for the development of appropriate treatments or preventions for memory dysfunction as we grow older. These treatments may also be beneficial in delaying some of the symptoms of Alzheimer’s Disease. One subtype of the glutamate receptors, the N-methyl-D-aspartate (NMDA) receptor, is expressed in high density in cortical and hippocampal regions and is very important in the initiation steps of learning and memory (5). NMDA receptors are involved in the performance of spatial, working, and passive avoidance memory tasks and in long-term potentiation (LTP), a cellular phenomenon that is believed to be involved in at least some types of memory. The NMDA receptors appear to be more vulnerable to the aging process than other glutamate receptors (6,7) and show declines in their binding densities, electrophysiological functions, and influence on other transmitter systems. The evidence suggests that these changes in NMDA receptor function should have an impact on learning and memory abilities and, in fact, several studies that demonstrate aging changes in the NMDA receptor also show a correlation between these changes and memory performance. This review will present the normal features and functions of the NMDA receptor complex, discuss the changes that have been reported in the NMDA receptor and its related functions during aging, and suggest future directions for improving or preventing age-related changes in learning and memory processes by targeting the NMDA receptor complex. Some of this information has been reviewed previously (8). This review represents an expansion of certain topics and an update on the progress achieved since 1994.

2.1. NMDA Receptor Complex

The NMDA receptor complex is a large protein assemblage that has multiple binding sites for different ligands, including an NMDA binding site, a strychnine-insensitive glycine binding site, and a binding site within the channel for certain noncompetitive antagonists; each of which can bind several different compounds (figure 1) (5,9). The NMDA site also binds L-glutamate and L-aspartate as endogenous agonists and D-2-amino-5-phosphonopentanoic acid (AP5), [(±)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid (CPP), CGP39653, and CGS19755 as antagonists. The glycine site binds serine and D-cycloserine, which act as agonists, and 7-chlorokynurenic acid (7-Cl-KYNA) is one antagonist for this site (10). Within the channel, non-competitive antagonists, such as (+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohept-5,10-imine maleate (MK801), ketamine, phencyclidine (PCP) and 1-(1-thienyl-cyclohexyl)piperidine (TCP); can bind. There are also binding sites on the receptor complex for polyamines, protons, redox reagents, zinc and magnesium that can modulate the activity of the receptor (figure 1) (5,9). These different binding sites and their interactions have been exploited to assess the effects of aging on the NMDA receptor complex.

Figure 1. Binding sites associated with the NMDA receptor complex. Other ligands used in the binding or functional studies referenced in this review are indicated in parentheses. Diagram adapted from Corsi, et al. (9).

The NMDA receptor has an absolute requirement of co-agonism for channel activity; both glutamate and glycine must occupy their binding sites for channel activation (9,11). However, agonist binding alone is insufficient to activate the channel because at hyperpolarized potentials the channel pore is blocked by magnesium (12). Repetitive synaptic activation, leading to neuronal depolarization, will relieve this block, allowing calcium to enter the neuron (12). This influx of calcium plays an important role in the induction of LTP, which may ultimately be expressed as learning (13,14).

2.2. Subunits

The functional subunits of the NMDA receptor complex have been cloned for rats (15-18), mice (19-22) and humans (23-25). There are two families of subunits identified for the NMDA receptor, in rats and humans they are termed the NMDAR1 (NR1; zeta1 for mice) and NMDAR2 (NR2; epsilon for mice) families. There is a 99% amino acid homology between the rat and human NR1 and the mouse zeta1 subunit (21-24,26). The NR1 subunit has the same distribution as NMDA-displaceable [³H]glutamate binding throughout the cortex and hippocampus (15,21,26). This subunit appears to be necessary and sufficient for the formation of functional channels and, in homomeric receptors, can respond to glutamate, glycine, and MK801 (16,17,20,21), suggesting the presence of these binding sites on the NR1 subunit. Mutational analysis also suggests that the glycine site is associated with the NR1 subunit (27).

There are at least four members of the NR2 family of subunits that show high homology between species (21,22,24) and are designated as NR2A-D for the rat (16,17) and human (24) and as epsilon1-4 for the mouse (19-21). The NR2A-D subunits each enhance the activity of the receptor when coupled with the NR1 subunit (16). The subtypes within this family of subunits confer different agonist/antagonist affinities to NR1/NR2 heteromeric receptors (20,22), as well as producing different gating behaviors, responses to Mg⁺⁺, and I/V curves (16,17). They also differ from each other and the NR1 subunit in distribution and developmental patterns of mRNA expression (16,17,20,21,28,29). The different spatiotemporal expressions of these subunits suggest that multiple NMDA receptor populations exist in the brain and that they differ both within and between brain regions.

2.3. Learning and Memory

The NMDA receptor appears to play an integral role in memory. Much of the evidence has been derived from studies on rodents performing spatial reference memory tasks; functional NMDA receptors have been shown, with antagonists and subunit-specific knockout mice, to be necessary for successful performance in the Morris water maze (30-34). In addition, correlations have been seen between NMDA-displaceable [³H]glutamate binding in prefrontal/frontal and hippocampal regions and reference memory performance in the Morris water maze (35,36). NMDA receptors also appear to be involved in some forms of passive avoidance learning (37) and in working memory functions; NMDA antagonists inhibit performance of spatial working memory tasks when a delay is induced between choices (38) and NMDA application to the prefrontal cortex of macaques increases the short term memory retention time (39). Long term potentiation (LTP) is a sustained increase in the efficiency of synaptic transmission that typically is induced by high-frequency stimulation (14,40). Antagonists of the NMDA receptor and knockouts of the NR1 gene block the initiation of LTP in both the hippocampus (14,33,34,41,42) and neocortex (43) and, in some studies, this has been associated with declines in spatial memory performance (33,34). These studies all demonstrate an important role for NMDA receptors in memory processes and suggest that detrimental changes to the NMDA receptor during the aging process may explain, at least in part, the memory declines that people and animals experience during the aging process.