title: Up-regulation of GLT1 expression increases glutamate uptake and attenuates the Huntington's disease phenotype in the R6/2 mouse.
abstract: The striatum, which processes cortical information for behavioral output, is a key target of Huntington's disease (HD), an autosomal dominant condition characterized by cognitive decline and progressive loss of motor control. Increasing evidence implicates deficient glutamate uptake caused by a down-regulation of GLT1, the primary astroglial glutamate transporter. To test this hypothesis, we administered ceftriaxone, a beta-lactam antibiotic known to elevate GLT1 expression (200 mg/kg, i.p., for 5 days), to symptomatic R6/2 mice, a widely studied transgenic model of HD. Relative to vehicle, ceftriaxone attenuated several HD behavioral signs: paw clasping and twitching were reduced, while motor flexibility, as measured in a plus maze, and open-field climbing were increased. Assessment of GLT1 expression in striatum confirmed a ceftriaxone-induced increase relative to vehicle. To determine if the change in behavior and GLT1 expression represented a change in striatal glutamate handling, separate groups of behaving mice were evaluated with no-net-flux microdialysis. Vehicle treatment revealed a glutamate uptake deficit in R6/2 mice relative to wild-type controls that was reversed by ceftriaxone. Vehicle-treated animals, however, did not differ in GLT1 expression, suggesting that the glutamate uptake deficit in R6/2 mice reflects dysfunctional rather than missing GLT1. Our results indicate that impaired glutamate uptake is a major factor underlying HD pathophysiology and symptomology. The glutamate uptake deficit, moreover, is present in symptomatic HD mice and reversal of this deficit by up-regulating the functional expression of GLT1 with ceftriaxone attenuates the HD phenotype.
authors: Program in Neuroscience, Department of Psychological and Brain Sciences, 1101 East 10th Street, Bloomington, IN 47405, USA.
authors: B R
authors: BR
authors: Miller
authors: J L
authors: JL
authors: Dorner
authors: M
authors: M
authors: Shou
authors: Y
authors: Y
authors: Sari
authors: S J
authors: SJ
authors: Barton
authors: D R
authors: DR
authors: Sengelaub
authors: R T
authors: RT
authors: Kennedy
authors: G V
authors: GV
authors: Rebec
mesh_terms: D000818:Animals; D002443:Ceftriaxone / Q000627:therapeutic use*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism*; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006816:Huntington Disease / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D009435:Synaptic Transmission / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D018698:Glutamic Acid; D002443:Ceftriaxone