• Top page
  • Timetable
  • Per session
  • Per presentation
  • How to
  • Meeting Planner



Conditional deletion of glial glutamate transporters in spinal cord induces ALS-like phenotypes in mice

  • P2-316
  • 杉山 香織 / Kaori Sugiyama:1 相田 知海 / Tomomi Aida:1 野村 政壽 / Masatoshi Nomura:2 高柳 涼一 / Ryoichi Takayanagi:2 田中 光一 / Kohichi Tanaka:1,3,4 
  • 1:東医歯大難治疾患研分子神経科学 / Mol Neurosci, Med Res Inst, Tokyo Med Dent Univ, Tokyo 2:九州大医病態制御内科学 / Dept Med and Bioreg Sci, Grad Sch of Med Sci, Kyushu Univ, Kyushu 3:東医歯大脳統合機能研セ / Cent Brain Integ Res, Tokyo Med Dent Univ, Tokyo 4:科学技術振興機構 CREST / JST, CREST, Saitama, Japan. 

Amyotrophic lateral sclerosis (ALS) is a fatal progressive motor neuron disease. Although 90% of ALS patients are sporadic cases, the pathogenic mechanisms that underlie sporadic ALS remain largely unknown. Loss of glial glutamate transporter, GLT1 and GLAST, has been repeatedly reported in ALS patients and animal models. Because both GLT1 and GLAST are responsible for glutamate clearance in synaptic cleft, dysfunction of these molecules increases extracellular glutamate concentration, leading to neuronal death by excitotoxicity. Consistent with this, elevated levels of glutamate are reported in the cerebrospinal fluid of 40% of ALS patients. Therefore, we hypothesized that loss of glial glutamate transporters in spinal cord is a primary cause for pathogenesis of sporadic ALS. To address this, we generated spinal cord specific glial glutamate transporters conditional knockout (cKO) mice by crossing floxed GLT1 mice with Hoxb8-Cre mice expressing Cre recombinase specifically in spinal cord, and GLAST knockout mice.
In cKO mice, 90% reduction of GLT1 protein and 50% reduction of GLAST protein were observed in lumbar region, but no difference in the cereberum. These mice exhibit progressive reduction of body weight, motor dysfunction, and finally hindlimb paralysis. At lumbar level, cKO mice showed glial activation, significant loss of motor neurons and axonal degeneration, but no abnormalities in sensory neurons in dorsal horn.
These results indicate that loss of glial glutamate transporters in spinal cord causes progressive and selective motor neuronal degeneration, leading to motor dysfunction relevant to ALS. Therefore, this novel mouse model will provide a unique opportunity for examining pathogenic mechanisms of sporadic ALS and their novel therapeutics.

Copyright © Neuroscience2014. All Right Reserved.