Aging Favors Calcium Activation of Ryanodine Receptor (RyR) Channels from Brain Cortex and Hippocampus and Hinders Learning and Memory in Male Rats

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Abstract
The response of ryanodine receptor (RyR) channels to increases in cytoplasmic calcium concentration ([Ca2+]) is tuned by several mechanisms, including redox signaling. Three different responses to [Ca2+] have been described in RyR channels, low, moderate and high activity responses, which depend on RyR channel protein oxidation state. Thus, reduced RyR channels display the low activity response, whereas partially oxidized channels display the moderate response and more oxidized channels, the high activity response. As described here, RyR channels from rat brain cortex or hippocampus displayed aged-related marked changes in the distribution of these channel responses; RyR channels from aged rats displayed reduced fraction of low activity channels and increased fraction of high activity channels, which would favor Ca2+-induced Ca2+ release. In addition, compared with young rats, aged rats displayed learning and memory defects, with lower hit rates when tested in the Oasis maze, a dry version of the Morris water maze. Previous oral administration of N-acetylcysteine for 3 weeks prevented both the age-dependent effects on RyR channel activation by [Ca2+] and the learning and memory defects. We propose that redox-sensitive neuronal RyR channels partake in the mechanism underlying the learning and memory disruptions displayed by aged rats.

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