Abstract
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 (PKCγ) 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 PKCγ is not only important but necessary for neuronal differentiation, neurite outgrowth and axonal branching but not for axonal extension. Mechanically, through the phosphorylation of GSK3β, PKCγ stabilizes the expression of cytosolic β-catenin and increase GAP43 expression, thus promoting axonal outgrowth. Further, rAAV2/9-mediated delivery of constitutive PKCγ in the corticospinal tract after unilateral TBI in vivo additionally showed that specifically delivery of active PKCγ mutant to cortical neuron promotes midline crossing of corticospinal fibers from the uninjured side to the denervated cervical spinal cord. This PKCγ-mediated injury response promoted sensorimotor functional recovery. In conclusion, PKCγ mediates stability of β-catenin through the phosphorylation of GSK3β to facilitate neuronal differentiation, neurite outgrowth and axonal branching, and PKCγ maybe a novel therapeutic target for physiological and functional recovery after TBI.
Highlights
Worldwide, traumatic brain injury (TBI) is estimated to impact 50 million people and produce a $400 billion-dollar healthcare burden annually[1]
SMI-31 and MAG immunoreactivity were mostly disappeared in the right dorsal CST (dCST) originating from the injured left cortex (Fig. 1b), indicating that unilateral Traumatic brain injury (TBI) resulted in a destruction of the corticospinal tract (CST) descending from the injured cortex
Immunofluorescence staining showed that phosphorylated PKCγ (p-PKCγ) was bilaterally expressed in the dCST of the cervical spinal cord in sham-operated mice, while a loss of p-PKCγ was observed in the right dCST after unilateral TBI
Summary
Traumatic brain injury (TBI) is estimated to impact 50 million people and produce a $400 billion-dollar healthcare burden annually[1]. It has been demonstrated that recovery of motor function is owed (at least in part) to the re-crossing of sprouting CST fibers (from the intact side) through the spinal midline[6,7], where they are believed to form compensatory motor fiber networks on the denervated side, contributing to the restoration of motor function after injury. The exogenous induction of STAT3 in a rodent model of CST lesion has shown a significant increase in the number of midline crossing fibers that have been shown to target short propriospinal and spinal motor neurons in the intermediate and ventral laminae of the spinal cord[8] Behavioral strategies such as bilateral movement training have demonstrated increases in CST midline crossing following TBI in rodents[9]. Optimizing molecular strategies for endogenous remodeling after injury could meaningfully alleviate the chronic symptoms of TBI
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