Knockdown of calpain1 in lumbar motoneurons reduces spasticity after spinal cord injury in adult rats.

Abstract

Spasticity, impacting about 75% of patients with spinal cord injury (SCI), leads to hyperreflexia, muscle spasms and co-contractions of antagonist muscles, greatly affecting their quality of life. Spasticity primarily stems from the hyperexcitability of motoneurons below the lesion, driven by an upregulation of the persistent sodium current and a downregulation of chloride extrusion. This imbalance results from the post-SCI activation of calpain1, which cleaves Nav1.6 channels and KCC2 co-transporters. Our study was focused on mitigating spasticity by specifically targeting calpain1 in spinal motoneurons. We successfully transduced lumbar motoneurons in adult rats with SCI, using intrathecal administration of adeno-associated virus AAV6, carrying a ShRNA sequence against calpain1. This approach significantly reduced calpain-1 expression in transduced motoneurons, leading to a noticeable decrease in spasticity symptoms including hyperreflexia, muscle spasms and co-contractions in hindlimb muscles, particularly evident in the second month post-SCI. Additionally, this decrease that prevented the escalation of spasticity to a severe grade, paralleled with the restoration of KCC2 levels in transduced motoneurons, suggesting a reduced proteolytic activity of calpain1. These findings demonstrate that inhibiting calpain1 in motoneurons is a promising strategy for alleviating spasticity in SCI patients.