Human Molecular Genetics Advance Access originally published online on August 5, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 19 2519-2532
DOI: 10.1093/hmg/ddg267
© 2003 Oxford University Press
Increased expression of the glial glutamate transporter EAAT2 modulates excitotoxicity and delays the onset but not the outcome of ALS in mice
1Department of Neuroscience, 2Ohio State Biochemistry Program, 3Neuroscience Graduate Studies Program and 4Integrated Biomedical Sciences Graduate Program, The Ohio State University, 4068 Graves Hall, 333 W. 10th Avenue, Columbus, OH 43210, USA
Received May 20, 2003; Revised July 19, 2003; Accepted July 30, 2003
The glial glutamate transporter EAAT2 is primarily responsible for clearance of glutamate from the synaptic cleft and loss of EAAT2 has been previously reported in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. The loss of functional EAAT2 could lead to the accumulation of extracellular glutamate, resulting in cell death known as excitotoxicity. However, it is still unknown whether it is a primary cause in the cascade leading to neuron degeneration or a secondary event to cell death. The goals of this study were to generate transgenic mice overexpressing EAAT2 and then to cross these mice with the ALS-associated mutant SOD1(G93A) mice to investigate whether supplementation of the loss of EAAT2 would delay or rescue the disease progression. We show that the amount of EAAT2 protein and the associated Na+-dependent glutamate uptake was increased about 2-fold in our EAAT2 transgenic mice. The transgenic EAAT2 protein was properly localized to the cell surface on the plasma membrane. Increased EAAT2 expression protects neurons from L-glutamate induced cytotoxicity and cell death in vitro. Furthermore, our EAAT2/G93A double transgenic mice showed a statistically significant (14 days) delay in grip strength decline but not in the onset of paralysis, body weight decline or life span when compared with G93A littermates. Moreover, a delay in the loss of motor neurons and their axonal morphologies as well as other events including caspase-3 activation and SOD1 aggregation were also observed. These results suggest that the loss of EAAT2 may contribute to, but does not cause, motor neuron degeneration in ALS.
* To whom correspondence should be addressed. Tel: +1 6146885433; Fax: +1 6146888742; Email: lin.492{at}osu.edu
The authors wish it to be known that, in their opinion, the first four authors should be regarded as joint First Authors.
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