Characterization of striatal lesions produced by glutamate uptake alteration: Cell death, reactive gliosis, and changes in GLT1 and GADD45 mRNA expression

This study investigated the time course of the striatal lesions produced by continuous local injection of the glutamate uptake inhibitor, L-trans-pyrr olidine-2,4-dicarboxylate (PDC) at the rate of 25 nmol/h in rats. The exten t of the neurodegeneration area (defined as the lesion area) did not signif icantly vary with the duration of the PDC treatment between 3 and 14 days, but was markedly reduced 3 months after cessation of the 14-day treatment, probably reflecting striatal atrophy. After the S-day treatment, the lesion zone showed calcium precipitates and marked microglial reaction contrastin g with the reduction of astroglial labeling and loss of the glutamate trans porter GLT1 mRNA expression; however reactive astrocytes were observed arou nd the lesion. After the 14-day treatment, the lesion zone presented reacti ve astrocytes and microglia without calcification, and a partial recovery o f GLT1 mRNA expression. Interestingly, the growth arrest DNA damage-inducib le GADD45 mRNA expression was induced around the lesion after 3 days but in side the lesion after 14 days of treatment. Three months after the 14-day t reatment, the astroglial reactivity persisted within the lesion whereas mos t of the other markers examined tended to normalize. These data suggest tha t defective glutamate transport induces primary death of neurons and dysfun ction of astrocytes. They strongly implicate reactive astrocytes with GLT1 and GADD45 transcripts in preventing secondary neuronal death. (C) 2000 Wil ey-Liss, Inc.