Age-related Loss of miR-124 Causes Cognitive Deficits via Derepressing RyR3 Expression

Epigenetic alterations of brain contribute to age-related cognitive decline. The challenge now is to identify these tractable epigenetic molecules working as the downstream cell-signaling nodes mediating age-related cognitive decline. Here we reported age-related loss of miR-124 in human and rat brains. To further validate these findings, knockout mice in which one of the three miR-124 genes (miR-124-3) was deleted using CRISPR/Cas9-mediated gene engineering were generated. MiR-124-3 knockout mice developed cognitive deficit phenotype. MiR-124 deficiency in the mouse brain resulted in upregulation of the Ryanodine receptor 3 (RyR3) gene, and the cognitive deficits in miR-124-3 knockout mice were ameliorated by knocking down RyR3 expression using RNAi. In addition, miR-124 deficiency facilitated Aβ42-induced neuron apoptosis. Our work suggested that age-related cognitive decline, at least in part, was associated with miR-124 deficiency and subsequently upregulated RyR3 expression in inducing neuronal death.