Spinal cord GLT-1 glutamate transporter and blood glutamic acid alterations in motor neuron degeneration (Mnd) mice.
This study characterizes for the first time neurochemical mechanisms in Mnd mice, initially described as a model of motor neuron disease and more recently proposed as a model for neuronal ceroid lipofuscinosis. A selective decrease (-30%) of [3H]glutamate uptake was found in spinal cord but not cortical synaptosomes of Mnd mice aged 28 weeks, when they show histopathological alterations, complete blindness and moderate neurological deficits. In spite of the widespread presence of stored material in neurons in many brain regions and spinal cord, the active transport of [3H]serotonin, [3H]dopamine and depolarization-induced [3H]serotonin release were not affected. Spinal EAAC1 glutamate transporter protein was significantly decreased in some but not all aged mice by 36% on average, possibly due to the loss of motor neurons. GLT-1 immunoreactivity was reduced by 34% in 28-week-old Mnd mice, while GLAST immunoreactivity was not affected. In Mnd mice aged 14 weeks, when there was no apparent alteration of motor function, the defect in the glial transporter protein GLT-1 was similar to that in 28-week-old mice (25%). Blood glutamic acid concentration was increased in Mnd mice aged 14-22 weeks. We suggest that the early decrease of GLT-1 protein might raise the extrasynaptic glutamic acid concentration, and contribute to the loss of motor neurons in affected mice, resulting in low [3H]glutamate uptake, low EAAC1 immunoreactivity and neurological deficits.
Mennini
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T
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy. tiziana@irfmn.mnegri.it
Bastone
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Crespi
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Comoletti
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Manzoni
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D018528:ATP-Binding Cassette Transporters / Q000032:analysis; D027322:Amino Acid Transport System X-AG; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018698:Glutamic Acid / Q000097:blood*; D006624:Hippocampus / Q000378:metabolism; D015151:Immunoblotting; D008297:Male; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009410:Nerve Degeneration / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism*
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D012701:Serotonin; D018698:Glutamic Acid; D004298:Dopamine