Ceftriaxone-induced up-regulation of cortical and striatal GLT1 in the R6/2 model of Huntington's disease.
BACKGROUND
Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by cortico-striatal dysfunction and loss of glutamate uptake. At 7 weeks of age, R6/2 mice, which model an aggressive form of juvenile HD, show a glutamate-uptake deficit in striatum that can be reversed by treatment with ceftriaxone, a beta-lactam antibiotic that increases GLT1 expression. Only at advanced ages (> 11 weeks), however, do R6/2 mice show an actual loss of striatal GLT1. Here, we tested whether ceftriaxone can reverse the decline in GLT1 expression that occurs in older R6/2s.


RESULTS
Western blots were used to assess GLT1 expression in both striatum and cerebral cortex in R6/2 and corresponding wild-type (WT) mice at 9 and 13 weeks of age. Mice were euthanized for immunoblotting 24 hr after five consecutive days of once daily injections (ip) of ceftriaxone (200 mg/kg) or saline vehicle. Despite a significant GLT1 reduction in saline-treated R6/2 mice relative to WT at 13, but not 9, weeks of age, ceftriaxone treatment increased cortical and striatal GLT1 expression relative to saline in all tested mice.


CONCLUSIONS
The ability of ceftriaxone to up-regulate GLT1 in R6/2 mice at an age when GLT1 expression is significantly reduced suggests that the mechanism for increasing GLT1 expression is still functional. Thus, ceftriaxone could be effective in modulating glutamate transmission even in late-stage HD.
Sari
Youssef
Y
Program in Neuroscience, Indiana University, 1101 East 10th Street, Bloomington, IN, USA.
Prieto
Anne L
AL
Barton
Scott J
SJ
Miller
Benjamin R
BR
Rebec
George V
GV
D000704:Analysis of Variance; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002443:Ceftriaxone / Q000494:pharmacology*; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D006816:Huntington Disease / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015854:Up-Regulation
D000900:Anti-Bacterial Agents; D027342:Excitatory Amino Acid Transporter 2; D002443:Ceftriaxone