PTEN deletion in spinal pathways via retrograde transduction with AAV-retro enhances forelimb motor recovery after cervical spinal cord injury; sex differences and late-onset pathophysiologies.

Spinal cord injuries (SCI) cause severe and long-lasting functional impairments due to interruption of motor and sensory pathways. Regeneration of axons does not occur due to intrinsic growth limitations of adult neurons and extrinsic inhibitory factors, especially at the injury site, but some regeneration can be achieved via deletion of the phosphatase and tensin homolog (PTEN). Here, deployed an AAV variant that is retrogradely transported to deliver (AAV-retro) to deliver gene modifying cargos to the cells of origin of pathways interrupted by SCI, testing whether this promoted recovery of motor function. We injected different titers of AAV-retro/Cre into the cervical spinal cord at C5 in PTEN f/f ;Rosa tdTomato mice and control Rosa tdTomato mice at the time of a C5 dorsal hemisection injury. Forelimb grip strength was tested over time using a grip strength meter. PTEN f/f ;Rosa tdTomato mice injected with AAV-retro/Cre exhibited substantial improvements in forelimb gripping ability in comparison to controls. Of note, there were major sex differences in the extent of recovery, with male mice exhibiting greater recovery than females. The values for male mice largely account for the overall differences between PTEN-deleted and controls. However, some PTEN-deleted mice began to exhibit pathophysiologies involving excessive scratching and rigid forward extension of the hindlimbs which we term "dystonia". These pathophysiologies increased over time. Our results reveal that although intra-spinal injections of AAV-retro/Cre in PTEN f/f ;Rosa tdTomato mice can enhance forelimb motor recovery after SCI, there are late-developing functional abnormalities with the experimental conditions used here. The mechanisms underlying these late-developing pathophysiologies remain to be defined.