Abstract
Rett Syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the Methyl CpG binding protein 2 (MECP2) gene. Deficient K+-Cl—co-transporter 2 (KCC2) expression is suggested to play a key role in the neurodevelopmental delay in RTT patients’ neuronal networks. KCC2 is a major player in neuronal maturation by supporting the GABAergic switch, through the regulation of neuronal chlorine homeostasis. Previous studies suggest that MeCP2 mutations lead to changed KCC2 expression levels, thereby causing a disturbance in excitation/inhibition (E/I) balance. To investigate this, we performed protein and RNA expression analysis on post mortem brain tissue from RTT patients and healthy controls. We showed that KCC2 expression, in particular the KCC2a isoform, is relatively decreased in RTT patients. The expression of Na+-K+-Cl− co-transporter 1 (NKCC1), responsible for the inward transport of chlorine, is not affected, leading to a reduced KCC2/NKCC1 ratio in RTT brains. Our report confirms KCC2 expression alterations in RTT patients in human brain tissue, which is in line with other studies, suggesting affected E/I balance could underlie neurodevelopmental defects in RTT patients.
Highlights
Rett syndrome (RTT) is a progressive neurodevelopmental disorder mainly affecting young girls
We found that all three RTT patients studied, show a lower K+-Cl—co-transporter 2 (KCC2) expression compared to healthy controls (Kruskal-Wallis test p = 0,0143, Fig. 2a)
Earlier studies investigated KCC2 level changes in RTT patient’s cerebrospinal fluid (CSF), in human iPSC-derived neurons and in motor cortex and cerebellar tissue of RTT patients [11, 15, 27]. These findings suggest involvement of KCC2 in disease mechanisms in RTT. In support of this hypothesis and to study the influence of Methyl-CpG-Binding-Protein 2 (MeCP2) on KCC2 levels in different brain areas, we investigated KCC2 expression in four different cortical areas and hippocampus of three RTT patients and age matched controls
Summary
Rett syndrome (RTT) is a progressive neurodevelopmental disorder mainly affecting young girls. We investigated KCC2 levels and KCC2/NKCC1 ratio in post mortem tissue of patients and controls in the areas Brodmann Area (BA) 4, BA6, BA10, BA20 and Hippocampus, using RNA and immunocytochemical analysis. We found that KCC2 expression is overall decreased in RTT patient post mortem tissue, suggesting playing a role in neuronal development.
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