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  • Wiley  (3)
  • Ludolph, Albert C.  (3)
  • Biodiversity Research  (3)
  • 1
    In: Journal of Neuroscience Research, Wiley, Vol. 71, No. 6 ( 2003-03-15), p. 819-825
    Abstract: Defective glutamate uptake has been implicated as a pathogenic event of neuronal damage related to cerebral ischemia and hypoxia. In several models of ischemia‐hypoxia, a reduced immunoreactivity and altered RNA expression of excitatory amino acid transporter 2 (EAAT2), the major excitatory amino acid transporter, have been reported. However, the gene regulation of EAAT2 under these conditions is incompletely understood. In this study, we investigated alternative splicing of EAAT2 in an in vivo mouse model of chemical hypoxia as induced by 3‐nitropropionic acid (3‐NP). The neurotoxin 3‐NP is an inhibitor of mitochondrial energy production. Furthermore, it is known to inhibit glutamate reuptake directly, representing at least one of the mechanisms responsible for 3‐NP‐induced neurodegeneration. Here we report an expression analysis of five known (mEAAT2/5UT1–5) and two novel (mEAAT2/5UT6, ‐7) 5′ splice variants of EAAT2 using semiquantitative PCR. The RNA expression was studied at 2, 12, 24, 48, and 72 hr and 7 days after 3‐NP administration. mEAAT2/5UT4 and mEAAT2/5UT5 were up‐regulated in the frontal cortex and down‐regulated in the hippocampus 12–72 hr after chemical hypoxia. In the cerebellum, there was an increased expression of mEAAT2/5UT4 and a down‐regulation of mEAAT2/5UT5. mEAAT2/5UT3 show a different regional expression pattern, being regulated in the cerebellum only. mEAAT2/5UT1–7 encoded distinct 5′ regulatory sequences, including conserved elements of translational control. It is easily conceivable that expression alterations of 5′ splice variants of EAAT2 are related to glutamate transporter malfunction after chemical hypoxia. Our findings contribute to the hypothesis that RNA splicing events can serve as a molecular mechanism of posthypoxic gene regulation. © 2003 Wiley‐Liss, Inc.
    Type of Medium: Online Resource
    ISSN: 0360-4012 , 1097-4547
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2003
    detail.hit.zdb_id: 1474904-X
    detail.hit.zdb_id: 195324-2
    SSG: 12
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  • 2
    In: European Journal of Neuroscience, Wiley, Vol. 26, No. 7 ( 2007-10), p. 1895-1901
    Abstract: In recent years, magnetic resonance imaging (MRI) has emerged as a preferred tool for the diagnosis of amyotrophic lateral sclerosis (ALS) in humans. A widely used animal model for human ALS is the G93A‐superoxide dismutase 1 (G93A‐SOD1) transgenic mouse model. However, the mechanisms for the selective degeneration of motor neurons in the brainstem and spinal cord are still uncertain. In our study, we applied MRI at 4.7 Tesla to non‐invasively evaluate pathological alterations in the brainstem of this animal model and to follow the progression of the disease. Extending previous investigation, we used the relaxation parameter T 2 as a suitable measure for the progression of ALS, and evaluated the potential agreement with histological evaluation and behavioural data of open‐field tests. In the brainstem of G93A‐SOD1 mice, T 2 values were significantly increased in the motor nuclei Nc. V, Nc. VII and Nc. XII, as early as Day 80, i.e. before the average disease onset at about Day 90. Moreover, this increase is associated with a progressive development of vacuoles in the brainstem motor nuclei and a significantly decreased performance in behavioural tests. Overall, MRI is a very sensitive tool to obtain correlates for neuronal degeneration in vivo . Furthermore, MRI enables us to investigate a follow up at different time points of the disease. These advantages are especially useful for therapeutic studies with respect to survival rates of motor neurons using mouse models. Finally, our data suggest that MRI does not only resemble the findings of behavioural tests, but is potentially superior to behavioural studies.
    Type of Medium: Online Resource
    ISSN: 0953-816X , 1460-9568
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2007
    detail.hit.zdb_id: 2005178-5
    detail.hit.zdb_id: 645180-9
    SSG: 12
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  • 3
    In: European Journal of Neuroscience, Wiley, Vol. 25, No. 6 ( 2007-03), p. 1669-1677
    Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. Visualizing corresponding metabolic changes in the brain of patients with ALS with proton magnetic resonance spectroscopy ( 1 H‐MRS) may provide surrogate markers for an early disease detection, for monitoring the progression and for evaluating a treatment response. The primary objective of our study was to evaluate whether modifications in MR metabolite levels occur before clinical disease onset, and whether these changes are directly linked to a distinct spatial progression pattern in the CNS. Therefore, age‐dependent alterations in the cerebral and spinal metabolic profile in the mouse model of ALS overexpressing the mutated human G93A‐superoxide dismutase 1 (G93A‐SOD1) were determined by high‐resolution MRS of tissue extracts at 14.1 Tesla. Both non‐transgenic mice (control mice) and transgenic mice overexpressing the non‐mutated human SOD1 (tg‐SOD1) served as controls. In the spinal cord of G93A‐SOD1 mice significantly decreased levels of N‐acetyl aspartate were already detected 34 days postpartum, i.e. about 60 days before the average disease onset caused by motor neuron decline. In addition, glutamine and γ‐aminobutyric acid concentrations were significantly diminished at Day 75, which is still in the presymptomatic phase of the disease. These metabolic changes were further progressive in the course of the disease and started to involve the brainstem at Day 75. Overall, high‐resolution 1 H‐MRS allows a sensitive spatial and temporal metabolite profiling in the presymptomatic phase of ALS even before significant neuronal cell loss occurs.
    Type of Medium: Online Resource
    ISSN: 0953-816X , 1460-9568
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2007
    detail.hit.zdb_id: 2005178-5
    detail.hit.zdb_id: 645180-9
    SSG: 12
    Location Call Number Limitation Availability
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