Hippocampal dependent learning ability correlates with N‐methyl‐D‐aspartate (NMDA) receptor levels in CA3 neurons of young and aged rats

Abstract

Hippocampal N-methyl-D-Aspartate (NMDA) receptors mediate mechanisms of cellular plasticity critical for spatial learning in rats. The present study examined the relationship between spatial learning and NMDA receptor expression in discrete neuronal populations, as well as the degree to which putative age-related changes in NMDA receptors are coupled to the effects of normal aging on spatial learning. Young and aged Long-Evans rats were tested in a Morris water maze task that depends on the integrity of the hippocampus. Levels of NR1, the obligatory subunit for a functional NMDA receptor, were subsequently quantified both biochemically by Western blot in whole homogenized hippocampus, and immunocytochemically by using a high-resolution confocal laser scanning microscopy method. The latter approach allowed comprehensive, regional analysis of discrete elements of excitatory hippocampal circuitry. Neither method revealed global changes, nor were there region-specific differences in hippocampal NR1 levels between young and aged animals. However, across all subjects, individual differences in spatial learning ability correlated with NR1 immunofluorescence levels selectively in CA3 neurons of the hippocampus. Parallel confocal microscopic analysis of the GluR2 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor failed to reveal reliable differences as a function of age or spatial learning ability. This analysis linking age, performance, and NR1 levels demonstrates that although dendritic NR1 is generally preserved in the aged rat hippocampus, levels of this receptor subunit in selective elements of hippocampal circuitry are linked to spatial learning. These findings suggest that NMDA receptor abundance in CA3 bears a critical relationship to learning mediated by the hippocampus throughout the life span.

Effect of age on kainate-induced seizure severity and cell death

“…Several studies have recognized age-related changes in the density and function of the different ionotropic glutamate receptors (Gonzales et al, 1991;Pittaluga et al, 1993;Nicoletti et al, 1995;Magnusson, 1998;Mitchell and Anderson, 1998;Wenk and Barnes, 2000). Although still somewhat controversial, many studies have shown that the expression of AMPA-, KA-and NMDA-sensitive receptors as well as the GABA A receptor is either constant or variably diminished in many different brain regions including the hippocampus during aging (Gonzales et al, 1991;Pittaluga et al, 1993;Le Jeune et al, 1996;Nicolle et al, 1996;EcklesSmith et al, 2000;Kuehl-Kovarik et al, 2000;Magnusson, 2000;Sonntag et al, 2000;Wenk and Barnes, 2000;Adams et al, 2001;Clayton and Browning, 2001;Clayton et al, 2002;Lerma et al, 2001). Differences in a variety of other factors, including voltage-gated calcium channels (Vigues et al, 1999;Kelly et al, 2003), androgen levels (Mejias-Aponte et al, 2002;Ramsden et al, 2003;Ciriza et al, 2004), and GABA receptor function (MacGregor et al, 1997;Ma et al, 2001) which have been shown to modulate kainate-induced seizure activity in young animals, may modulate susceptibility in aged animals as well.…”

Neurobiological and Endocrine Correlates of Individual Differences in Spatial Learning Ability

“…to correlate with the levels of the NR1 subunit of the NMDA receptor in the dendrites of CA3 hippocampal pyramidal cells (Adams et al 2001). Animals with better spatial learning ability had higher NR1 levels than subjects with poorer scores on the task.…”

“…Moreover, activity within the hippocampus during encoding has also been shown to correlate, across individuals, with performance on tests of memory tasks (for review, see Tulving et al 1999). Evidence indicates that rats can considerably differ in their spatial learning abilities, a phenomenon particularly prominent at senescence (Rowe et al 1998;Schulz et al 2002), but also observable in early adulthood (Adams et al 2001;Sandi et al 2003a;Venero et al 2004). Recent reports support the view that individual differences in the acquisition of the hippocampus-dependent learning task the Morris water maze (Morris et al 1982;Riedel et al 1999) are associated with a differential modulation of specific hippocampal circuits.…”

“…Recent reports support the view that individual differences in the acquisition of the hippocampus-dependent learning task the Morris water maze (Morris et al 1982;Riedel et al 1999) are associated with a differential modulation of specific hippocampal circuits. Both in young and aged rats, the abundance of the NR1 subunit of the NMDA receptor in the dendrites of CA3 pyramidal cells was reported to correlate with performance variability during maze learning, with animals that performed better exhibiting higher NR1 levels (Adams et al 2001). Moreover, we recently found the inverse correlation between learning ability and synaptic density at the level of the contacts between mossy fiber terminals and proximal apical dendrites from CA3 pyramidal cells observed 24 h following a massed training protocol, with synaptic levels being higher in rats that exhibited a poorer acquisition curve (Sandi et al 2003a).…”

Theta-Frequency Synaptic Potentiation in CA1In VitroDistinguishes Cognitively Impaired from Unimpaired Aged Fischer 344 Rats

“…In these experiments, a second train of 5 Hz stimulation applied in the same slice 50 min after APV washout resulted in complex spiking (total spike number, 98 Ϯ 12) and robust LTP [158 Ϯ 6%; n ϭ 7(4)] that was comparable with that seen in naïve young slices [162 Ϯ 7%; n ϭ 17(8)]. Because NMDAR subunit expression is depressed in aged rats (Davis et al, 1993;Adams et al, 2001), we considered the possibility that the selective impairment in 5 Hz LTP in AI rats reflected a reduced capacity for LTP induction. To address this question directly, we examined NMDAR-mediated responses in young, AU, and AI rats.…”