Microgravity‐Induced Cognitive Decline: Investigating the Pathogenic Mechanisms of <scp>RyR2</scp> Hyperphosphorylation and <scp>S107</scp> Intervention

Cognitive function is crucial for astronauts to successfully complete space missions. Therefore, investigating the mechanisms by which one of the primary stressors in the space environment-microgravity-affects cognitive function is of great significance. Although synaptic plasticity is recognized as being highly associated with cognitive function, the mechanisms underlying its changes under microgravity remain unclear. Here, using a hindlimb unloading (HU) model in mice, we investigated the effects of short-term (7 days) and long-term (28 days) HU on cognitive function. We found that long-term HU significantly affected cognitive performance, as evidenced by impaired spatial learning and memory, reduced long-term potentiation (LTP), and decreased dendritic spine density in the 28-day HU group, while no such changes were observed in the 7-day HU group. Proteomic analysis focusing on synaptic subregions revealed that metabolic and oxidative phosphorylation signal pathways were significantly upregulated, whereas signal pathways related to synaptic organization and cation transport were markedly downregulated. Notably, we identified increased phosphorylation of the calcium-regulating protein RyR2 (ryanodine receptor 2) as a key alteration. Furthermore, continuous treatment with the RyR2 stabilizer S107 from days 7 to 28 during HU effectively prevented HU-induced cognitive decline in mice. In summary, our study provides the first evidence that microgravity-induced cognitive impairment is mediated by excessive phosphorylation of RyR2.