AGE-RELATED DEFICITS IN EXPRESSION OF THE N-METHYL-D-ASPARTATE 2B RECEPTOR SUBUNIT CORRELATES WITH BEHAVIORAL IMPAIRMENT IN FISHER 344 RATS.
M.H. Mesches*1,2,3; D.A. Clayton2,4*; L Veng2 ;C.A. Rabiner1,3; C. Allgeier1,3; P.C. Bickford1,2,3; M.D. Browning2,3
1. VAMC, Denver, CO, 80220 USA 2. Neuroscience Program, 3. Department of Pharmacology, UCHSC, Denver, CO, 80262 USA, 4. Medical Scientist Training Program
Aging is associated with a decline in learning and memory . Recent studies have suggested that the hippocampus and N-methyl-D-aspartate receptor (NMDAR) undergo age-related changes. Previous studies reported age-related decreases in the expression of the NMDAR subunit NR2B protein and messenger RNA (mRNA). The objective of the present study was to correlate the hippocampal expression of the NMDAR in relation to impairment in a spatial learning task. Expression of the NMDAR subunit proteins, NR1, NR2A, and NR2B was measured as well as the expression of the AMPA receptor subunit GluR2. Protein levels were measured by quantitative Western blotting and mRNA levels were measured using kinetic reverse transcription polymerase chain reaction in male Fischer 344 rats. Behavioral testing was performed on young (4 mo) and aged 18 -24 mo) animals using the Morris water maze. Behavioral scores were assigned to each animal based upon their performance in 3 trials per day for 10 days. Expression patterns were examined by ANOVA for effects by age and by subunit. Expression levels were also tested for correlations with established learning indices. The NR2B subunit showed statistically significant decreases in protein and mRNA levels in aged versus young animals. Importantly, levels of NR2B expression correlated with behavioral scores.
Given the multitude of age-related changes in the mammalian brain, we decided to attempt to determine the role of reduced hippocampal NR2B subunit expression on hippocampal function. To selectively reduce NR2B subunit expression, antisense NR2B mRNA (asNR2B) was injected into the hippocampus of young (6 mo) F344 rats. N2RB protein levels, hippocampal plasticity [early and late phase long term potentiation (LTP), and primed burst potentiation (PB)], and spatial learning and memory were examined in separate groups of rats. Single unilateral infusions of asNR2B, but not scrambled mRNA or vehicle, significantly decreased NR2B protein levels and LTP and PB in a time-dependent manner compared to the contralateral hippocampus. Protein levels of NR2A were unaffected by the asNR2B infusions. Moreover, spatial learning was significantly impaired 3 d after bilateral asNR2B infusions, when NR2B protein levels were at their lowest levels. These findings underscore the role of the NR2B subunit in hippocampal function.
These findings also complement the results of transgenic experiments that demonstrated improved performance in spatial learning tasks in mice that overexpressed the NR2B subunit and impaired performance in NR2B knockout mice. This is the first report of a direct comparison between performance in spatial learning and memory and NR2B levels. Our findings are consistent with Sonntag et al., who have also reported age-related deficits in hippocampal NR2B levels as well as improved performance in spatial learning following treatments that enhance hippocampal NR2B levels in aged animals.
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