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Synaptosomal glutamate transport studies in a transgenic rat model of amyotrophic lateral sclerosis
Author(s) -
McIlvain H. B.,
She Y.,
Howland D. S.,
Dunlop J.
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.81.s1.20_13.x
Subject(s) - riluzole , amyotrophic lateral sclerosis , glutamate receptor , sod1 , spinal cord , chemistry , medicine , superoxide dismutase , endocrinology , biology , pharmacology , neuroscience , biochemistry , oxidative stress , receptor , disease
Transgenic rats over‐expressing the G93A Co/Zn superoxide dismutase (SOD1) mutation have recently been generated (Howland et al. PNAS 99 , 1604–1609) and found to replicate an amyotrophic lateral sclerosis (ALS) – like motor neuron disease previously described in transgenic mice harboring the same mutation. Impairments in synaptosomal glutamate transport capacity have been documented both in the transgenic mouse model and with tissue obtained from human ALS patients. We have measured synaptosomal glutamate transport in the G93A SOD1 rat to further characterize these animals and to provide a comparison with the data described above. We observed a 36% decrease in the maximum velocity of glutamate uptake in synaptosomes prepared from spinal cord of G93A SOD1 rats compared with age matched control animals (Vmax values for glutamate transport were 152 and 98 pmol/min/mg, respectively, in control and transgenic animals) while the affinity for glutamate (Km 3–5 μ m ) was unchanged. In contrast, no differences in V max values were observed when synaptosomes were prepared from cortex, hippocampus, striatum, brainstem or cerebellum. Pharmacological sensitivity to the selective GLT‐1 transport inhibitor dihydrokainate (IC50 74 μ m ) demonstrates that glutamate uptake in spinal cord synaptosomes is predominantly mediated by this subtype. Incubation of spinal cord synaptosomes with riluzole (100 μ m ) resulted in a 20–30% increase in glutamate uptake in the control animals while in the G93A SOD1 rats this effect was less pronounced. Our results indicate both a reduction in spinal cord glutamate transport capacity in the SOD1 rats and an altered functional response to riluzole.