Restoration of motor neuron function via potassium channels in SMA mice

Movement and muscle control are regulated by the activity of motor neurons which are located in the spinal cord. Spinal motor neurons convey central commands to their peripheral targets, the skeletal muscles. Pre-motor neurons make synaptic contacts with motor neurons and regulate their function. However, the molecular mechanisms underlying synaptic-mediated motor neuron function are unknown. To address this, we use in vivo and in vitro models of spinal muscular atrophy a neurodegenerative disease caused by deficiency of the ubiquitously expressed SMN protein. Proximal muscles are preferentially affected during the progression of this disease, compared to more distal muscles. In our proposal, we aim to investigate enzymatic effects on the molecular and cellular function of potassium channels expressed on the motor neurons. Potassium channels are essential to elicit repetitive firing of motor neurons and subsequent muscle contraction. Utilizing enzyme inhibitors that regulate the activity of potassium channels, we aim to uncover the cascade of molecular events leading to the enhancement of motor neuron function. Our study has the potential to reveal salient principles in the restoration of neuronal function in spinal muscular atrophy and offer novel therapeutic avenues.