Modulation of Extrinsic and Intrinsic Signaling Together with Neuronal Activation Enhances Forelimb Motor Recovery after Cervical Spinal Cord Injury

Singular strategies for promoting axon regeneration and motor recovery after spinal cord injury (SCI) have been attempted with limited success. For instance, the deletion of <i>RhoA</i> and phosphatase and tensin homolog (<i>Pten</i>) (an extrinsic and intrinsic modulating factor, respectively) in corticospinal neurons (CSNs) promotes axon sprouting after thoracic SCI; however, it is unable to restore motor function. Here, we examine the effects of combining <i>RhoA/Pten</i> deletion in CSNs with chemogenetic neuronal stimulation on axonal growth and motor recovery after SCI in mice. We find that this combinatorial approach promotes greater axonal growth and presynaptic bouton formation in CSNs within the spinal cord compared with <i>RhoA</i>;<i>Pten</i> deletion alone. Furthermore, chemogenetic neuronal stimulation of <i>RhoA</i>;<i>Pten</i>-deleted CSNs improves forelimb performance in behavioral tasks after SCI compared with <i>RhoA</i>;<i>Pten</i> deletion alone. These results demonstrate that combination therapies pairing genetic modifications with neuronal stimulation can promote greater presynaptic formation and motor recovery following SCI than either strategy alone.