title: Downregulation of the potassium chloride cotransporter KCC2 in vulnerable motoneurons in the SOD1-G93A mouse model of amyotrophic lateral sclerosis.
abstract: The balance between excitatory and inhibitory synaptic inputs is critical for the physiological control of motoneurons. The maintenance of a low-intracellular chloride concentration by the potassium chloride cotransporter 2 (KCC2) is essential for the efficacy of fast synaptic inhibition of mature motoneurons in response to the activation of ionotropic γ-aminobutyric acid A and glycine receptors. Altered synaptic balance and excitotoxicity have been proposed as candidate pathophysiological processes in amyotrophic lateral sclerosis (ALS). Therefore, we investigated the expression patterns of KCC2 and its functional opponent, the chloride influx-mediating sodium-potassium chloride cotransporter 1 (NKCC1), in the superoxide dismutase 1 (SOD1-G93A) mouse model of ALS. We detected reduced KCC2 messenger RNA levels and less membrane-bound KCC2 immunoreactivity in ALS-vulnerable motoneurons in lumbar spinal cord and hypoglossal nuclei of SOD1-G93A mice but not in degeneration-resistant oculomotor nuclei. Downregulation of KCC2 started during late presymptomatic stages and accelerated in parallel to hind limb and tongue motor function deficits. In contrast, NKCC1 messenger RNA levels were unaltered in postnatal lumbar spinal cord motoneurons. Our data indicate that reductions in KCC2 gene expression may contribute to selective motor deficits and disease progression in vulnerable motoneurons in a mouse model of ALS.
authors.affiliation: Institute of Neurophysiology, Goethe-University, Frankfurt, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fuchs
authors.forename: Cornelia
authors.initials: C
authors.lastname: Ringer
authors.forename: Andras
authors.initials: A
authors.lastname: Bilkei-Gorzo
authors.forename: Eberhard
authors.initials: E
authors.lastname: Weihe
authors.forename: Jochen
authors.initials: J
authors.lastname: Roeper
authors.forename: Burkhard
authors.initials: B
authors.lastname: Schütz
mesh_terms: D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001933:Brain Stem / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics*; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism; D000096922:K Cl- Cotransporters
chemical_list: D012333:RNA, Messenger; D013482:Superoxide Dismutase; D027981:Symporters; D050494:Vesicular Acetylcholine Transport Proteins; D000096922:K Cl- Cotransporters; C493460:Slc18a3 protein, mouse; C109415:SOD1 G93A protein