Reversing Persistent PTEN Activation after Traumatic Brain Injury Fuels Long‐Term Axonal Regeneration via Akt/mTORC1 Signaling Cascade

Traumatic brain injury (TBI) often leads to enduring axonal damage and persistent neurological deficits. While PTEN's role in neuronal growth is recognized, its long-term activation changes post-TBI and its effects on sensory-motor circuits are not well understood. Here, it is demonstrated that the neuronal knockout of PTEN (PTEN-nKO) significantly enhances both structural and functional recovery over the long term after TBI. Importantly, in vivo, DTI-MRI revealed that PTEN-nKO promotes white matter repair post-TBI. Additionally, calcium imaging and electromyographic recordings indicated that PTEN-nKO facilitates cortical remapping and restores sensory-motor pathways. Mechanistically, PTEN negatively regulates the Akt/mTOR pathway by inhibiting Akt, thereby suppressing mTOR. Raptor is a key component of mTORC1 and its suppression impedes axonal regeneration. The restoration of white matter integrity and the improvements in neural function observed in PTEN-nKO TBI-treated mice are reversed by a PTEN/Raptor double knockout (PTEN/Raptor D-nKO), suggesting that mTORC1 acts as a key mediator. These findings highlight persistent alterations in the PTEN/Akt/mTORC1 axis are critical for neural circuit remodeling and cortical remapping post-TBI, offering new insights into TBI pathophysiology and potential therapeutic targets.