title: Transgenic SOD1 G93A mice develop reduced GLT-1 in spinal cord without alterations in cerebrospinal fluid glutamate levels.
abstract: Glutamate-induced excitotoxicity is suggested to play a central role in the development of amyotrophic lateral sclerosis (ALS), although it is still unclear whether it represents a primary cause in the cascade leading to motor neurone death. We used western blotting, immunocytochemistry and in situ hybridization to examine the expression of GLT-1 in transgenic mice carrying a mutated (G93A) human copper-zinc superoxide dismutase (TgSOD1 G93A), which closely mimic the features of ALS. We observed a progressive decrease in the immunoreactivity of the glial glutamate transporter (GLT-1) in the ventral, but not in the dorsal, horn of lumbar spinal cord. This effect was specifically found in 14- and 18-week-old mice that had motor function impairment, motor neurone loss and reactive astrocytosis. No changes in GLT-1 were observed at 8 weeks of age, before the appearance of clinical symptoms. Decreases in GLT-1 were accompanied by increased glial fibrillary acidic protein (GFAP) levels and no change in the levels of GLAST, another glial glutamate transporter. The glutamate concentration in the cerebrospinal fluid (CSF) of TgSOD1 G93A mice was not modified at any of the time points examined, compared with age-matched controls. These findings indicate that the loss of GLT-1 protein in ALS mice selectively occurs in the areas affected by neurodegeneration and reactive astrocytosis and it is not associated with increases of glutamate levels in CSF. The lack of changes in GLT-1 at the presymptomatic stage suggests that glial glutamate transporter reduction is not a primary event leading to motor neurone loss.
authors.affiliation: Department of Neuroscience Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy. bendotti@maionegri.it
authors.forename: C
authors.initials: C
authors.lastname: Bendotti
authors.forename: M
authors.initials: M
authors.lastname: Tortarolo
authors.forename: S K
authors.initials: SK
authors.lastname: Suchak
authors.forename: N
authors.initials: N
authors.lastname: Calvaresi
authors.forename: L
authors.initials: L
authors.lastname: Carvelli
authors.forename: A
authors.initials: A
authors.lastname: Bastone
authors.forename: M
authors.initials: M
authors.lastname: Rizzi
authors.forename: M
authors.initials: M
authors.lastname: Rattray
authors.forename: T
authors.initials: T
authors.lastname: Mennini
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001522:Behavior, Animal; D015153:Blotting, Western; D004195:Disease Models, Animal; D018450:Disease Progression; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000097:blood / Q000134:cerebrospinal fluid*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism
chemical_list: D027322:Amino Acid Transport System X-AG; D027342:Excitatory Amino Acid Transporter 2; D005904:Glial Fibrillary Acidic Protein; D012333:RNA, Messenger; D018698:Glutamic Acid; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase