Brain microstructural abnormalities correlate with KCC2 downregulation in refractory epilepsy

Dysregulations in the expression level of Na-K-Cl cotransporter (NKCC1) and K-Cl cotransporter (KCC2) genes have been detected in the brain tissues of patients with refractory epilepsy. Given the importance of these proteins in the determination of Cl- equilibrium potential (E-Cl), evaluation of the expression changes of these transporters might assist in optimizing the diagnostic approaches and therapeutic strategies. The present investigation evaluates the expression level chloride transporters in polymorphonuclear cells and their correlation with microstructural abnormalities. Thirty cases of drug-resistant epilepsy (confirmed with temporal lobe epilepsy diagnosis) fulfilled the considered inclusion criteria. Cases were divided into two groups, one with a detectable MRI lesion (19 participants; right side) and another with no MRI findings (11 participants). Whole-brain voxel-based analysis was performed on diffusion tensor imaging to measure fractional anisotropy and mean diffusivity; neurite orientation dispersion and density imaging was performed to map neurite density index and orientation dispersion index. Our results indicated that fractional anisotropy and mean diffusivity changed in temporal and extratemporal parts of the brain, whereas the changes in neurite density index and orientation dispersion index were exclusively obvious in the temporal lobe. Molecular studies revealed significantly lower levels of KCC2 expression in patients with epilepsy, a finding that remarkably correlated with microstructural changes as well. Our research showed that downregulation of KCC2 and microstructural abnormalities might contribute to the observed refractoriness in temporal lobe epilepsy.