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The Journal of Neuroscience, March 1, 2003, 23(5):1688

Impaired Spinal Cord Glutamate Transport Capacity and Reduced Sensitivity to Riluzole in a Transgenic Superoxide Dismutase Mutant Rat Model of Amyotrophic Lateral Sclerosis

John Dunlop¹, H. Beal McIlvain¹, Yijin She², and David S. Howland²

¹ Neuroscience and ² Molecular Genetics, Wyeth Research, Princeton, New Jersey 08543-8000

We characterized synaptosomal glutamate transport activity in a recently developed transgenic rat model of amyotrophic lateral sclerosis (ALS) overexpressing the G93A Cu²⁺/Zn²⁺ superoxide dismutase (SOD1) mutation. Using spinal cord synaptosomes, a significant reduction (43%) in the maximal velocity for high-affinity, Na⁺-dependent glutamate uptake was observed at disease end stage in G93A rats compared with age-matched controls. Similarly, a 27% reduction in maximum velocity (V_max) was measured at disease onset, but no difference in spinal cord V_max values were observed with presymptomatic animals compared with controls. In comparison, we observed no differences in the V_max for glutamate clearance at disease end stage with synaptosomes from cortex, hippocampus, striatum, cerebellum, and brainstem, indicating a specific deficit in the spinal cord. The pharmacological sensitivity of spinal cord uptake to dihydrokainate suggests that the GLT-1 (glutamate transporter-1) subtype primarily mediates the transport activity. Expression analysis revealed a loss of GLT-1 as well as qualitative changes in GLAST (glutamate/aspartate transporter) but no measurable changes in EAAC1 (excitatory amino acid carrier 1) in spinal cord of end-stage G93A rats, indicating that deficits in glutamate transporters in this rat model may be glial specific. Riluzole, a neuroprotective agent used clinically to slow the progression of ALS, produced an enhancement of spinal cord synaptosomal glutamate uptake in control animals and early-stage disease G93A rats, but this effect was lost in end-stage animals. Altered expression of astroglial glutamate transporters accompanied by reduced capacity for spinal cord clearance of extracellular glutamate in the G93A SOD1 transgenic rat may account for a dampened effect of riluzole to enhance glutamate uptake at end-stage disease.

Key words: Cu²⁺/Zn²⁺ superoxide dismutase; ALS; GLT-1; GLAST; glutamate; riluzole

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2351688-09$05.00/0

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