Infants and adults respond differently to brain injuries. Specifically, improved neuronal sparing along with reduced astrogliosis and glial scarring often observed earlier in life, likely contributes to improved long-term outcomes. Understanding the underlying mechanisms could enable the recapitulation of neuroprotective effects, observed in infants, to benefit adults after brain injuries. We reveal that in primates, Eph/ ephrin signaling contributes to age-dependent reactive astrocyte behavior. Ephrin-A5 expression on astrocytes was more protracted in adults, whereas ephrin-A1 was only expressed on infant astrocytes. Furthermore, ephrin-A5 exacerbated major hallmarks of astrocyte reactivity via EphA2 and EphA4 receptors, which was subsequently alleviated by ephrin-A1. Rather than suppressing reactivity, ephrin-A1 signaling shifted astrocytes towards GAP43+ neuroprotection, accounting for improved neuronal sparing in infants. Reintroducing ephrin-A1 after middle-aged focal ischemic injury significantly attenuated glial scarring, improved neuronal sparing and preserved circuitry. Therefore, beneficial infant mechanisms can be recapitulated in adults to improve outcomes after CNS injuries.

婴儿和成人对脑损伤的反应不同。具体来说，在生命早期经常观察到的神经元保留的改善以及星形胶质细胞增生和胶质瘢痕的减少可能有助于改善长期结果。了解潜在机制可以重现在婴儿中观察到的神经保护作用，从而使脑损伤后的成年人受益。我们揭示在灵长类动物中，Eph/ephrin 信号传导有助于年龄依赖性反应性星形胶质细胞行为。成人星形胶质细胞上的 Ephrin-A5 表达更持久，而 ephrin-A1 仅在婴儿星形胶质细胞上表达。此外，ephrin-A5通过增强星形胶质细胞反应性的主要标志EphA2 和 EphA4 受体，随后被 ephrin-A1 缓解。ephrin-A1 信号不是抑制反应性，而是将星形胶质细胞转向 GAP43+ 神经保护，从而改善婴儿的神经元保留。中年局灶性缺血性损伤后重新引入 ephrin-A1 可显着减轻神经胶质瘢痕形成、改善神经元保留和保留电路。因此，可以在成人中概括有益的婴儿机制，以改善 CNS 损伤后的结果。