Abstract
Spinal cord injury (SCI) often causes severe and permanent disabilities. The current study uses a transneuronal approach to stimulate spinal cord regeneration by AAV-hyper-IL-6 (hIL-6) application after injury. While preinjury PTEN knockout in cortical motoneurons fails to improve functional recovery after complete spinal cord crush, a single, postinjury injection of hIL-6 into the sensorimotor cortex markedly promotes axon regeneration in the corticospinal and, remarkably, raphespinal tracts enabling significant locomotion recovery of both hindlimbs. Moreover, transduced cortical motoneurons directly innervate serotonergic neurons in both sides of the raphe nuclei equally, enabling the synaptic release of hIL-6 and the transneuronal stimulation of raphe neurons in the brain stem. Functional recovery depends on the regeneration of serotonergic neurons as their degeneration induced by a toxin abolishes the hIL-6-mediated recovery. Thus, the transneuronal application of highly potent cytokines enables functional regeneration by stimulating neurons in the deep brain stem that are otherwise challenging to access, yet highly relevant for functional recovery after SCI.
