This study examined high affinity Na+-dependent uptake of glutamate in synaptosomal preparations from spinal cord in mice that express a dominant mutation of human copper/zinc superoxide dismutase (SOD1) and represent an animal model of amyotrophic lateral sclerosis (ALS). Their muscle strength was also monitored by a grip traction test throughout their lifespan. The high affinity Na+-dependent uptake of [3H]glutamate was decreased between 120 and 150 days of age. A marked and significant decrease in Vmax (-40.2%; p < 0.001) on whole spinal cord synaptosomes was observed at 150 days, with no change in Km. This significant decrease was reached a week before the animals died (157.2 +/- 2.2 days) and corresponded to a considerable fall in muscle strength (25% loss between 120 and 140 days, p < 0.001). The FALS mouse model therefore reproduces the decrease in glutamate uptake reported in humans suffering from sporadic or familial ALS. These results are discussed in terms of a possible tardive involvement of glutamate uptake deficiency in human ALS.