Calpain : a new target for the treatment of spasticity after a spinal cord injury. – CalpaSCI

After spinal cord injury (SCI) patients develop spasticity, a motor disorder characterized by hyperreflexia and stiffness of muscles. Spasticity results from alterations in motoneurons with an upregulation of their persistent sodium current (INaP), simultaneously with a disinhibition due to a reduced expression of chloride (Cl-) co-transporters KCC2. Up to now the origin of alterations is unknown. Meanwhile, it was established that the proteases calpains are activated in the spinal cord after injury. The typical response of Na+ channels to proteases is an increase in INaP, whereas modulation of KCC2 expression results from a dysregulation of Cl- homeostasis. In muscles, spasticity induces stiffness by calpain activation and remodeling of structural protein such as titin. The proposal will test the exciting possibility that proteolysis of the triad (Na+ channels, KCC2 and titin) by calpains represents the main mechanism responsible for spasticity. To this end we will: 1) characterize the time-course expression/activation of calpains after SCI 2) gain a better understanding of the mechanisms by which SCI-induced activation of calpains leads to spasticity 3) evaluate whether training, known to reduce spasticity, down-regulates the activation of calpains 4) demonstrate that preventing the action of calpains at the time of injury in the chronic phase of SCI, reduces the excitatory/inhibitory imbalance and stiffness of the muscles. Ultimately, an effective and minimally invasive treatment of spasticity will be designed by pharmacological or genetic tools (e.g. intramuscular injection of recombinant adenovirus associated vectors). The project will bring together two groups, located on the same campus, with complementary expertise. First, the two groups work on distinctly part of the neuromuscular system - the Brocard team on the motoneuron and the Bartoli team on the muscle. Second, the two groups have developed models and master expertise in different, yet complementary, experimental methodologies (electrophysiology, immunostaining, molecular biology, imaging, genomic, behaviour). This new collaboration is well suited for the fourth societal challenge “life, health and well-being”. It should provide both basic knowledge on SCI ethiopathology and open new avenues towards innovative therapeutics in a so far unexplored field.