C113 - xCT/Slc7a11 deletion accelerates functional recovery and improves histological outcomes following cervical spinal contusion in mice

xCT protein is the specific subunit of System xc-, a multi-proteic complex importing cystine into cell while releasing extracellular glutamate. Although xCT protein expression is detected in brain glial cells, its expression in the spinal cord and during spinal cord disorders remain elusive. According to preliminary data, xCT/Slc7a11 mRNA is upregulated in the early phase following spinal cord injury (SCI) in mice. The aim of this study is to examine the contribution of xCT to functional and histological outcomes following SCI, using wild-type mice (xCT+/+) and genetically-invalidated mice (xCT-/-). While xCT+/+ and xCT-/- mice partly recovered motor functions, contused xCT-/- mice recovered muscular grip strength as well as pre-SCI weight substantially faster than xCT+/+ mice. Histology of injured spinal cords revealed increased number of motor neurons in xCT-/- mice at multiple distances around lesion epicenter. As xCT has been demonstrated as a regulator of microglial function (Mesci et al., Brain, 2015), we assessed markers of microglial activation. At 2 weeks post-SCI, the number of type A Iba1+cells was unexpectedly much higher in contused xCT-/- than in xCT+/+spinal cords. Analysis of M1/M2 polarization showed that contused xCT-/- spinal cords contained higher mRNA levels of Ym1 and IGF-1 (M2) while lower levels of NOX2 and TNF-a (M1). Additionally, the number of astrocytes and oligodendrocytes were unchanged between the two injured groups. This study suggests that, following SCI trauma, an early xCT upregulation (if confirmed at the protein level) exacerbates microglia-driven inflammation and compromises spinal motor neuron survival.