Aging Favors Calcium Activation of Ryanodine Receptor Channels from Brain Cortices and Hippocampi and Hinders...

The response of ryanodine receptor (RyR) channels to increases in free 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 the 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 cortices or hippocampi 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. Based on these results, it is proposed that redox-sensitive neuronal RyR channels partake in the mechanism underlying the learning and memory disruptions displayed by aged rats.