Changes in mRNA in the dorsal root ganglion after CNS injury and intramuscular neurotrophin-3 treatment. Rattus norvegicus

Brain and spinal injury often impair sensorimotor processing in the spinal cord and reduce mobility. We established that complete transection of corticospinal pathways in the pyramids leads to increased spasms, excessive mono- and polysynaptic spinal reflexes and impaired locomotion in rats. Intramuscular neurotrophin-3 treatment at a clinically-feasible time-point after injury reduced these signs of spasticity. We found Neurotrophin-3 reduced spastic movements and improved neurophysiological sensorimotor control. Furthermore, the balance of inhibitory and excitatory synapses in the cord and the level of an ion transporter in motor neuron membranes required for normal reflexes were normalized. We discovered that Neurotrophin-3 is transported in sensory afferents from muscles to the dorsal root ganglia. Using genome-wide RNA sequencing of the whole cervical level 6-8 dorsal root ganglia, we explored mRNA changes in afferent neurons that were present 10 weeks after bilateral pyramidotomy. Many of the dysregulated genes are involved in axon guidance and plasticity. Intramuscular neurotrophin-3 treatment normalized many of those gene changes and may be one of the mechanisms how reflexes, functional recovery and molecular markers in the spinal cord are restored. This identifies neurotrophin-3 as a therapy that treats the underlying causes of spasticity and not only its symptoms. Overall design: RNA-Seq was performed on whole C6-8 dorsal root ganglia of six rats from three different groups: naïve rats, rats 10 weeks after bilateral pyramidotomy lesions and AAV1-GFP treatment into the muscle, rats 10 weeks after bilateral pyramidotomy lesions and AAV1-prepro-neurotrophin-3 treatment into the muscle. Differential expression was analyzed between each of the groups.