Transactive response DNA-binding protein of 43 kDa (TDP-43) is a nuclear DNA/RNA-binding protein involved in gene transcription and mRNA processing. Recently, TDP-43 has been found in the cytoplasmic inclusions observed in amyotrophic lateral sclerosis. Substantial attention has been devoted to the toxic effects of the cytoplasmic TDP-43 aggregates, whereas the functional role of this protein remains poorly investigated. Interestingly, TDP-43 could be localized in the synapse and affect synaptic plasticity and locomotion in Drosophila. Here, we would like to understand if TDP-43 could modulate spinal cord plasticity in a mouse model of neurotoxic motoneuron depletion. Therefore, the expression levels of TDP- 43 and synaptic proteins such as synapsin-I and the α-amino-3-hydroxy-5-methyl-4- isoxazolepropionate (AMPA) receptor subunits GluR1, GluR2 and GluR4 were measured by western blotting. By using multivariate regression models, protein expression levels were correlated each other as well as with the motor performance. The results suggested that motor performance could be linked to the expression of synapsin-I, and that the latter could depend on TDP-43, which in turn could interact with AMPA receptors. In conclusion, our results suggest that TDP-43 is likely involved in the modulation of synaptic plasticity. Given the increasing interest in mouse models of TDP-43 gain or loss of function in neurodegenerative diseases, the elucidation of the role of TDP-43 in the spinal cord is mandatory. More generally, given the recently increased knowledge about spinal cord plasticity, we postulate that the stimulation of the intrinsic plastic potential of spinal cord would be a successful repairing strategy.