Hypothalamic lncRNA Synage prevents age-related sperm quality decline by suppressing A-type potassium currents in GnRH neurons

Age-related decline in male fertility, including diminished sperm quality, poses significant risks to offspring health and is exacerbated by modern trends toward delayed parenthood. Focusing on the hypothalamus–pituitary–testis axis, which governs hormonal control of male reproduction, we identified Synage , a long noncoding RNA expressed in the hypothalamic medial preoptic area (mPOA). We found that Synage expression in gonadotropin-releasing hormone (GnRH) neurons decreases with age, correlating with reduced sperm quality and male fertility. mPOA-targeted Synage _B (brain-specific isoform) supplementation increases serum testosterone and improves sperm count and progressive motility in 12-mo-old mice. Conversely, conditional deletion of Synage in GnRH neurons in young mice reduces GnRH neuron firing, decreases serum LH and testosterone levels, impaires sperm quality, and reduces male fertility. Mechanistically, Synage interacts with the heat shock protein HSPA8 and stabilizes the HSPA8–KCHIP4 interaction. Synage loss increases KCHIP4 abundance and its association with the Kv4.2 channel, promoting Kv4.2 membrane recruitment and enhancing A-type potassium currents ( I A ), thereby reducing GnRH neuronal excitability. Consistent with this model, GnRH neurons from 12-mo-old mice also exhibit reduced excitability. Together, these findings support a role for age-dependent Synage loss in reproductive decline, at least in part through dysregulation of the HSPA8–KCHIP4–Kv4.2 pathway and reduced GnRH neuron excitability. These findings identify Synage as a candidate regulator of reproductive aging and motivate further investigation of its translational potential.