Brain research. Molecular brain research
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Brain Res. Mol. Brain Res. · May 2004
Loss of glial fibrillary acidic protein results in decreased glutamate transport and inhibition of PKA-induced EAAT2 cell surface trafficking.
Loss of the astrocyte-specific intermediate filament protein, glial fibrillary acidic protein (GFAP) results in an increased susceptibility to ischemic insult, enhanced hippocampal LTP, and decreased cerebellar long-term depression (LTD). Because glutamate receptor activation plays a key role in cell death and cellular plasticity responses, we wanted to determine if alterations in glial glutamate transport could contribute to the GFAP null phenotype. To address functional changes in glutamate transport, we measured glutamate uptake in cortical, cerebellar, and hippocampal synaptosomal preparations from age-matched adult wild type and GFAP null mice and demonstrated a 25-30% reduction in the V(max) for d-aspartate uptake in the cortex and hippocampus of GFAP null animals. ⋯ Immunohistochemical analysis demonstrated a region-specific modification of neuronal glutamate transporter, EAAT3 trafficking in the GFAP null phenotype. Analysis of primary cortical astrocyte cultures prepared from GFAP null and wild type mice demonstrated that loss of GFAP results in an inability to traffic the glial glutamate transporter, EAAT2, to the surface of the cell following protein kinase A (PKA) stimulation by dibutyryl cAMP. Taken together, these results suggest that the intermediate filament protein, GFAP plays a key role in modulating astrocytic and neuronal glutamate transporter trafficking and function.
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Brain Res. Mol. Brain Res. · Apr 2004
Doxycycline and protein folding agents rescue the abnormal phenotype of familial CJD H187R in a cell model.
Familial Creutzfeldt-Jakob disease (CJD) comprises a group of neurodegenerative disorders for which currently there is no treatment. In this study, we evaluated the efficacy of drugs approved for human use, and protein folding agents in reversing the mutant phenotype of familial CJD H187R in a cell model. For an efficient experimental readout, green fluorescent protein (GFP)-tagged mutant prion protein (PrP(187R-GFP)) and wild-type PrP (PrP(C-GFP)) were expressed in human neuroblastoma cells. ⋯ The concentration of doxycycline used in these studies is well within the plasma concentration of patients receiving a 250-600 mg dose two to three times daily. Interestingly, exposure of PrP(187R-GFP) cells to low temperature (28 degrees C) or to the chemical chaperones dimethyl sulphoxide (DMSO) and glycerol also reversed the mutant phenotype. These data suggest that doxycycline and protein folding agents may hold promise as therapeutic agents for familial CJD H187R and other familial disorders that share similar pathogenic mechanisms.
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Brain Res. Mol. Brain Res. · Feb 2004
Comparative StudyMice with reduced brain-derived neurotrophic factor expression show decreased choline acetyltransferase activity, but regular brain monoamine levels and unaltered emotional behavior.
The "neurotrophin hypothesis" of depression predicts that depressive disorders in humans coincide with a decreased activity and/or expression of brain-derived neurotrophic factor (BDNF) in the brain. Therefore, we investigated whether mice with a reduced BDNF expression due to heterozygous gene disruption demonstrate depression-like neurochemical changes or behavioral symptoms. BNDF protein levels of adult BDNF(+/-) mice were reduced to about 60% in several brain areas investigated, including the hippocampus, frontal cortex, striatum, and hypothalamus. ⋯ Moreover, BDNF(+/-) mice exhibited normal corticosterone and adrenocorticotropic hormone (ACTH) serum levels under baseline conditions and following immobilization stress. In a panel of behavioral tests investigating locomotor activity, exploration, anxiety, fear-associated learning, and behavioral despair, BDNF(+/-) mice were indistinguishable from wild-type littermates. Thus, a chronic reduction of BDNF protein content in adult mice is not sufficient to induce neurochemical or behavioral alterations that are reminiscent of depressive symptoms in humans.
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Brain Res. Mol. Brain Res. · Nov 2003
In vivo heat-shock response in the brain: signalling pathway and transcription factor activation.
We analysed the expression of the hsp70 gene, the phosphorylation status of different members of the mitogen-activated protein kinase (MAPK) family, the behaviour of the Akt-GSK3 pathway, as well as the DNA-binding activity of several transcription factors, potential targets of these kinases, in the brain of rats exposed to a fever-like increase in body temperature. Two different brain regions, the cerebellum and the hippocampus, were studied. Hyperthermia caused HSF activation and the induction of hsp70 mRNA and protein to a greater extent in the cerebellum than in the hippocampus. ⋯ Our data indicate that a physiologically relevant increase in body temperature induces brain injury and survival response to it as demonstrated by induction of hsp70 gene expression and activation of specific signalling pathways. Reprogramming of gene expression, by the specific transcription factors activated, probably plays a central role in cell adaptation and survival to heat stress. The hippocampus shows less responsiveness to hyperthermia than the cerebellum.
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Brain Res. Mol. Brain Res. · Oct 2003
Gene expression profiling of melanocortin system in neuropathic rats supports a role in nociception.
The melanocortin (MC) system is involved in several biological functions. Its possible role in nociception has recently attracted attention in the field. Published data suggest that melanocortin antagonists are analgesic and agonists are hyperalgesic. ⋯ MC4 and POMC transcript were upregulated in the spinal cord of neuropathic rats, whereas MC3 and AgRP expression were unaffected. Thus, this study demonstrates for the first time the presence of AgRP in the spinal cord and DRG, suggesting that it could play a role in the regulation of MC system activity. In addition, the upregulation of POMC and MC4, in parallel with the presence of tactile allodynia and thermal hyperalgesia, further supports the idea of MC system involvement in nociception.