AGE-RELATED INCREASE IN L-TYPE CALCIUM CHANNEL PROTEIN IN THE HIPPOCAMPUS CORELATES WITH SPATIAL WORKING MEMORY IMPAIRMENT





L. M. Veng*, M.H. Mesches, M.D. Browning

Neuroscience Training Program and Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado 80262



L-type voltage sensitive calcium channel (L-VSCC) currents are increased in the aged hippocampus. These currents cause excessive calcium flux in aged neurons and are thought to contribute to increases in the threshold for induction of long-term potentiation, a putative cellular mechanism of memory formation. We have previously reported that the L-VSCC subunit protein alpha1D is increased in area CA1 of aged rats. In the present study we tested the hypothesis that the age-related increase in hippocampal alpha1D expression is detrimental to spatial working memory in the radial arm water maze. Young (4 mo) and aged (24 mo) Fischer 344 rats were trained to find a submerged platform in a radial arm water maze. Rats underwent 7 days of pretraining to learn the non-hippocampal dependent demands of the task. Following pretraining, rats were tested for 4 days for their ability to find the submerged platform in one of 12 arms of the maze. The platform location changed between days but remained the same for all 4 trials in a given day. Young and aged rats were equally proficient in locating the hidden platform during these 4 days of testing. In order to study age differences in working memory for the hidden platform, we next introduced a 3 h delay between trials 3 and 4 and tested the rats for another 4 days using this paradigm. Aged rats made significantly more errors than young rats in locating the hidden platform on the 4th trial when there was a 3 h delay between the 3rd and 4th trials. These results show that aged rats have a deficit in working memory following a 3 h delay. Next, we performed semi-quantitative western blotting analysis to determine expression of alpha1D protein in CA1 of the hippocampus of the behaviorally characterized rats. Again we found that levels of alpha1D protein were significantly elevated in area CA1 of aged rats. Furthermore, levels of alpha1D protein significantly correlated with degree of working memory deficit in the radial arm water maze. These results suggest that age-related deficits in working memory might, in part, be due to over-expression of alpha1D protein in the aged hippocampus and point to excessive calcium influx in hippocampal neurons as a molecular mechanism of age-related cognitive decline.




Key words: calcium, memory, hippocampus, CA1







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