Calpain fosters the hyperexcitability of motoneurons after spinal cord injury and leads to spasticity

Abstract

Up-regulation of the persistent sodium current (INaP) and down-regulation of the potassium/chloride extruder KCC2 lead to spasticity after spinal cord injury (SCI). We here identified calpain as the driver of the up- and down-regulation of INaP and KCC2, respectively, in neonatal rat lumbar motoneurons. Few days after SCI, neonatal rats developed behavioral signs of spasticity with the emergence of both hyperreflexia and abnormal involuntary muscle contractions on hindlimbs. At the same time, in vitro isolated lumbar spinal cords became hyperreflexive and displayed numerous spontaneous motor outputs. Calpain-I expression paralleled with a proteolysis of voltage-gated sodium (Nav) channels and KCC2. Acute inhibition of calpains reduced this proteolysis, restored the motoneuronal expression of Nav and KCC2, normalized INaP and KCC2 function, and curtailed spasticity. In sum, by up- and down-regulating INaP and KCC2, the calpain-mediated proteolysis of Nav and KCC2 drives the hyperexcitability of motoneurons which leads to spasticity after SCI.

The M-current works in tandem with the persistent sodium current to set the speed of locomotion

“…The rhythm-generating network is a set of pacemaker cells endowed with intrinsic bursting activity in a frequency range similar to stepping rhythms [3,4]. In exploring the ionic basis for rhythmogenesis, we identified the persistent sodium current (I NaP ) as a critical current in burst-generating mechanism [5][6][7][8]. The immediate assumption was that the locomotor rhythm may emerge from neurons incorporating I NaP as a "pacemaker" current.…”

Enhancing KCC2 activity decreases hyperreflexia and spasticity after chronic SCI

“…Under normal physiological conditions, intracellular concentration of chloride is maintained low by the chloride extruder KCC2, which favors chloride influx through GABA A R and membrane hyperpolarization . After chronic SCI, there is a decrease in KCC2 expression in lumbar motoneurons (Boulenguez et al, 2010), likely via increased calpainmediated proteolysis (Plantier et al, 2019). This leads to a reversal of GABA-mediated responses from hyperpolarization to depolarization, and increases the chance that a motoneuron will fire an action potential (Vinay and Jean-Xavier, 2008;Boulenguez et al, 2010).…”

Differential effects of spinal cord transection on glycinergic and GABAergic synaptic signaling in sub-lesional lumbar motoneurons

“…Note that the expression rates of NKCC1, which decreases from P5 to low levels in adult spinal MNs (Still et al 2009), are not significantly affected by SCI in adult rats (Boulenguez et al, 2010;Cote et al, 2012). A restoration of KCC2 levels has been observed in SCT adult rats using sensorimotor strategies (Chopek et al, 2015;Cote et al, 2014;Khalki et al, 2018) or pharmacological treatments with the KCC2 activator prochlorperazine (Liabeuf et al, 2017) or the calpain inhibitor MDL28170 (Plantier et al, 2019). The effect of this up-regulation is twofold.…”

“…The effect of this up-regulation is twofold. It allows 1) a strengthening of inhibition through the preserved GlyR and chloride homeostasis and 2) a decrease of MNs hyperexcitability which resulted from the up-regulation of the persistent sodium current (INap) responsible for spasms (Brocard et al, 2016;Plantier et al, 2019).…”