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

Abstract

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.