Intramuscular Neurotrophin-3 normalizes low threshold spinal reflexes, reduces spasms and improves mobility after bilateral corticospinal tract injury in rats

Abstract

Brain and spinal injury reduce mobility and often impair sensorimotor processing in the spinal cord leading to spasticity. Here, we establish that complete transection of corticospinal pathways in the pyramids impairs locomotion and leads to increased spasms and excessive mono- and polysynaptic low threshold spinal reflexes in rats. Treatment of affected forelimb muscles with an adeno-associated viral vector (AAV) encoding human Neurotrophin-3 at a clinically-feasible time-point after injury reduced spasticity. Neurotrophin-3 normalized the short latency Hoffmann reflex to a treated hand muscle as well as low threshold polysynaptic spinal reflexes involving afferents from other treated muscles. Neurotrophin-3 also enhanced locomotor recovery. Furthermore, the balance of inhibitory and excitatory boutons in the spinal cord and the level of an ion co-transporter in motor neuron membranes required for normal reflexes were normalized. Our findings pave the way for Neurotrophin-3 as a therapy that treats the underlying causes of spasticity and not only its symptoms.DOI: http://dx.doi.org/10.7554/eLife.18146.001

RNAseq dataset describing transcriptional changes in cervical sensory ganglia after bilateral pyramidotomy and forelimb intramuscular gene therapy with AAV1 encoding human neurotrophin-3

“…The data presented here are related to the research article entitled "Intramuscular Neurotrophin-3 normalizes low threshold spinal reflexes, reduces spasms and improves mobility after bilateral corticospinal tract injury in rats" [1]. We now present additional data that were gathered as part of that work.…”

“…Twenty-four hours later, rats received unilateral injection into their forelimb flexors of either an Adeno-associated viral vector (AAV1) encoding human neurotrophin-3 (NT3) or Green Fluorescent Protein (GFP). These rats underwent behavioural testing, neurophysiological assessment and nerve tracing and tissues were recovered for histology as described elsewhere [1]. Owing to the facts that we found evidence that intramuscular neurotrophin-3 affects spinal networks via proprioceptive afferents, we decided to investigate transcriptional changes in the ipsilateral cervical DRGs.…”

“…For example, Gas7 and Sprr1a, cytoskeletal and growth cone modelling proteins, were both found downregulated after injury, but were normalized with neurotrophin-3 ( Figure 3). These and other genes may mediate sprouting of afferent (vGluT1 + ) fibres supraspinal injury and neurotrophin-3 treatment [1].…”

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Unilateral or bilateral corticospinal tract injury in the pyramids of adult rats causes changes in proprioceptive axon terminal arborization in the cervical spinal cord accompanied by hyperreflexia and abnormal movements including spasms [1,2]. Treatment of affected forelimb muscles with an Adeno-Associated Viral Vector (AAV) encoding human neurotrophin-3 (NT3) normalizes many of these anatomical, neurophysiological and behavioural changes [1]. Interestingly, in several studies, neurotrophin-3 protein accumulates in cervical dorsal root ganglia (DRG) on the side ipsilateral to AAV injection [1,3].

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“…Treatment of affected forelimb muscles with an Adeno-Associated Viral Vector (AAV) encoding human neurotrophin-3 (NT3) normalizes many of these anatomical, neurophysiological and behavioural changes [1]. Interestingly, in several studies, neurotrophin-3 protein accumulates in cervical dorsal root ganglia (DRG) on the side ipsilateral to AAV injection [1,3]. We hypothesize that neurotrophin-3 induces these changes (in proprioceptive axon wiring, proprioceptive reflex neurophysiology and sensorimotor behaviors involving proprioception) by modifying gene expression in affected cervical dorsal root ganglia (DRG).…”