Spasticity is a motor disorder following spinal cord injury (SCI). One of the main clinical manifestation is hypertonia associated with hyper-reflexia (i.e. overactive motor response to external stimuli) and for which there is no satisfactory cure. We recently demonstrate (Brocard et al., 2016, Nature Medicine) that the spasticity results from an excessive excitability of spinal motoneurons due to an upregulation of their persistent sodium current (INaP). Of special interest, we demonstrated that sodium channels are cleaved by a cysteine protease calpain which prevents their inactivation. As a result, INaP is increased. However, the mechanisms responsible for the activation of calpains remain fully unknown. In the healthy spinal cord, the excitability of motoneurons is set by brainstem-derived serotonin (5-HT) but a direct implication of brainstem serotonergic neurons in the development of spasticity, has not been explored so far. Our preliminary data show that activation of 5-HT2 receptors prevents cleavage of sodium channels after SCI (decrease of the distinct ~120-kDa band illustrated in the figure below). The proposal for the Master student will be to test the hypothesis that the lack of 5-HT contribute to spasticity through a calpain-mediated mechanism. The issue will be investigated in intact rats daily treated with p-chlorophenyalanine (PCPA) to block 5-HT synthesis. This model will mimic a deletion of 5-HT observed after SCI but without the mechanical injury. By means of a multidisciplinary approach (electrophysiology, immunostaining, and behavior) the consequences of silencing 5-HT neurons over an extended period will be examined on the emergence of the spasticity, the expression/activation of calpains and on the relative amount of sodium channels proteolysed.
Schematic representation of the lack of 5-HT in the sublesional spinal cord after SCI. On the top right corner, Western blots of lumbar spinal cords stained for a-subunit sodium channels from SCI rats treated with vehicle (SCI) or a serotoninergic agonist of 5hT2 receptors, the 2,5Dimethoxy4-iodoamphetamine (SCI+DOI). The ~250-kDa and the ~120-kDa bands correspond to the native and the cleaved sodium channels respectively.