Neurons in the central nervous system (CNS) lose regenerative potential with maturity, leading to minimal corticospinal tract (CST) axon regrowth after spinal cord injury (SCI). In young rodents, knockdown of PTEN, which antagonises PI3K signalling by hydrolysing PIP3, promotes axon regeneration following SCI. However, this effect diminishes in adults, potentially due to lower PI3K activation leading to reduced PIP3. This study explores if increased PIP3 generation can promote long-distance regeneration in adults. We used a hyperactive PI3K, PI3Kδ (PIK3CD), to boost PIP3 levels in mature cortical neurons and assessed CST regeneration after SCI. Adult rats received AAV1-PIK3CD and AAV1-eGFP, or AAV1-eGFP alone, in the sensorimotor cortex concurrent with a C4 dorsal SCI. Transduced neurons showed increased pS6 levels, indicating elevated PI3K/Akt/mTOR signalling. CST regeneration, confirmed with retrograde tracing, was evaluated up to 16 weeks post-injury. At 12 weeks, ∼100 axons were present at lesion sites, doubling to 200 by 16 weeks, with regeneration indices of 0.1 and 0.2, respectively. Behavioural tests showed significant improvements in paw reaching, grip strength, and ladder rung walking in PIK3CD-treated rats, corroborated by electrophysiological recordings of cord dorsum potentials and distal flexor muscles EMG. Thus, PI3Kδ upregulation in adult cortical neurons enhances axonal regeneration and functional recovery post-SCI.

中文翻译：

---

PI3Kinase 的高活性 delta 亚型可实现成年大鼠皮质脊髓束的长距离再生。


中枢神经系统 （CNS） 中的神经元随着成熟而失去再生潜力，导致脊髓损伤 （SCI） 后皮质脊髓束 （CST） 轴突再生最小。在年轻的啮齿动物中，敲除 PTEN，它通过水解 PIP3 拮抗 PI3K 信号传导，促进 SCI 后的轴突再生。然而，这种影响在成人中减弱，可能是由于 PI3K 激活降低导致 PIP3 降低。本研究探讨了增加的 PIP3 生成是否可以促进成人的远距离再生。我们使用过度活跃的 PI3K、PI3Kδ （PIK3CD） 来提高成熟皮层神经元的 PIP3 水平，并评估 SCI 后的 CST 再生。成年大鼠在感觉运动皮层中接受 AAV1-PIK3CD 和 AAV1-eGFP，或单独接受 AAV1-eGFP，同时伴有 C4 背侧 SCI。转导的神经元显示 pS6 水平升高，表明 PI3K/Akt/mTOR 信号升高。通过逆行追踪确认的 CST 再生在受伤后长达 16 周进行评估。12 周时，病变部位出现 ∼100 个轴突，到 16 周时翻倍至 200 个，再生指数分别为 0.1 和 0.2。行为测试显示，PIK3CD 处理的大鼠的爪子伸展、握力和梯级行走有显着改善，脊髓背电位和远端屈肌肌电生理记录证实了这一点。因此，成年皮层神经元中 PI3Kδ 的上调增强了 SCI 后的轴突再生和功能恢复。