Pkc Gamma Promotes Axonal Remodeling In The Cortico-Spinal Tract Via Gsk3 Beta/Beta-Catenin Signaling After Traumatic Brain Injury

Traumatic brain injury (TBI) is a common cause of death and disability. Enhancing the midline-crossing of the contralateral corticospinal tract (CST) to the denervated side of spinal cord facilitates functional recovery after TBI. Activation of the gamma isoform of PKC (PKC gamma) in contralateral CST implicates its roles in promoting CST remodeling after TBI. In this study, we deployed loss and gain of function strategies in N2a cells and primary cortical neurons in vitro, and demonstrated that PKC gamma is not only important but necessary for neuronal differentiation, neurite outgrowth and axonal branching but not for axonal extension. Mechanically, through the phosphorylation of GSK3 beta, PKC gamma stabilizes the expression of cytosolic beta-catenin and increase GAP43 expression, thus promoting axonal outgrowth. Further, rAAV2/9-mediated delivery of constitutive PKC gamma in the corticospinal tract after unilateral TBI in vivo additionally showed that specifically delivery of active PKC gamma mutant to cortical neuron promotes midline crossing of corticospinal fibers from the uninjured side to the denervated cervical spinal cord. This PKC gamma-mediated injury response promoted sensorimotor functional recovery. In conclusion, PKC gamma mediates stability of beta-catenin through the phosphorylation of GSK3 beta to facilitate neuronal differentiation, neurite outgrowth and axonal branching, and PKC gamma maybe a novel therapeutic target for physiological and functional recovery after TBI.