Maladaptive Remodeling of the Neuromuscular Synapse Following Central Nervous System Injury - PROJECT SUMMARY / ABSTRACT Central nervous system (CNS) injuries such as stroke and spinal cord injury (SCI) are major contributors to the global burden of disability. Attenuating CNS damage represents the core of research and neurorehabilitation strategies to enhance recovery. Yet, mounting evidence of peripheral nervous system (PNS) alterations after CNS injury provides an untapped area for therapeutic investigation. The PNS links CNS motor output with skeletal muscle function, where motor unit recruitment and firing rate modulate control. A motor unit is comprised of one motoneuron and all myofibers it innervates. For precision of motor control, healthy myofibers receive one motoneuronal axon via a single neuromuscular junction (NMJ). Studies suggest profound motor unit loss in paretic muscle after stroke and SCI, though exact mechanisms are undefined. Moreover, the applicant recently identified striking NMJ remodeling after stroke, including aberrant polyaxonal innervation (PAI), where NMJs receive more than one axonal input. Pilot data in SCI demonstrate motor unit losses similar to stroke, but impacts of SCI at the NMJ remain unexplored. Taken together, this project will interrogate maladaptive PNS remodeling in the context of CNS injury disability. This work will test the therapeutic potential of targeting paretic NMJs with brain-derived neurotrophic factor (BDNF), a known mediator of motor neuron viability and NMJ plasticity. In murine models of stroke and SCI, the applicant will longitudinally study motor behavior, motor unit electro- physiology, and muscle contractility; assess histopathology of motoneuron pools and NMJs; employ molecular biology techniques to define mechanisms of PAI; and validate a novel gene therapy approach. Aim 1 will test the hypothesis that SCI induces motor unit dysfunction and NMJ remodeling, similar to stroke. Aim 2 will define pathophysiological mechanisms of stroke-induced motor unit loss; some predict motoneuron degeneration is responsible, however we hypothesize re-expression of developmental mediators induces motor unit overlap, with PAI presenting electrophysiologically as spurious motor unit loss. Aim 3 will test the hypothesis that post- stroke reduction in BDNF signaling drives PAI, while normalization of BDNF via adeno-associated viral delivery restores NMJ form and motor function. Mentored training in translational neuromuscular physiology from the Sponsor (a neuromuscular specialist with extensive preclinical/clinical experience in neuromuscular health and disease) is complemented by a gene therapy specialist in CNS/PNS diseases as Co-Sponsor, and supported by two key Collaborators (an SCI physician-scientist, and a neuroscientist with BDNF signaling expertise). This mentorship team dovetails with the excellent resources and environment at The Ohio State University to facilitate growth in new areas of investigation and prepare the applicant for independence. Using clinically-relevant approaches to interrogate peripheral mechanisms of motor dysfunction after CNS injury, this project will expand the fundamental understanding of stroke and SCI disability, inform future therapeutics targeting peripheral alterations, and offer critical training opportunities for career development in academic neurological research.
