Limb movement in mammals and humans is governed by the ability of motor neurons to fire repetitively. Sensory proprioceptive neurons exert a major influence on the motor neurons firing frequency through expression of the delayed voltage rectifier potassium channel Kv2.1 during early development. In the most severe mouse model of spinal muscular atrophy (SMA-Δ7), vulnerable motor neurons exhibit significant reductions of Kv2.1 expression and impaired ability to fire repetitively. However, the mechanisms underlying the regulation of motor neuron firing by proprioceptive synapses is not well understood. In our study, we investigated the influence of enzymes known to modulate Kv2.1 expression in healthy and mutant SMA mice. Protein phosphatases and cyclin-dependent kinases, have been previously reported for their involvement in molecular trafficking of potassium channels in neuronal populations. We pharmacologically modulated the activity of a specific subset of these enzymes in vivo, by administering daily intraperitoneal injections in neonatal control and SMA-Δ7 mice, beginning at P0. We found significant improvements in the righting reflex by P10, as well as an extension in the life span of the SMA mice. Physiological monosynaptic spinal reflexes from vulnerable lumbar (L1/L2) spinal segments in intact ex vivo spinal cord preparations at P10 were significantly enhanced in SMA-treated mice, and a concomitant enrichment of the proprioceptive glutamatergic synapses on vulnerable motor neurons. These results uncover an important role of these enzyme modulators in improving synaptic numbers and transmission within select sensory-motor circuits. The presynaptic improvements resulted in substantial postsynaptic expression of Kv2.1 channels on motor neurons. In addition, the pharmacological treatments improved the amplitude of compound muscle action potential from the vulnerable muscle Quadratus Lumborum at P13, a late stage of disease in SMA mice. The treatment regimens resulted in a significant alleviation of neuromuscular junction denervation, simultaneously contributing to a recovery of the fast fatigable muscle fiber type at the vulnerable proximal musculature. Our study reveals that pharmacological modulation of the potassium channel Kv2.1 restores physiological function of the vulnerable motor neurons as well as the neuromuscular junctions in the SMA-Δ7 mouse model, providing significant benefits at the behavioral, neuronal and peripheral circuit level.