15869527

pubmed:Citation

8

Excitatory amino acid transporters (EAATs) maintain the balance between pathological and physiological conditions by limiting the extracellular concentration of glutamate within the CNS and thus preventing excitotoxic injury. The loss of EAAT2 has been associated with the development of neurological diseases such as amyotrophic lateral sclerosis. It has therefore been suggested that the over-expression of specific EAATs may provide some degree of neuroprotection. However, the inability to isolate and study the function of the different EAAT isoforms in a cell type-specific manner has made it difficult to determine the exact contribution of individual EAATs toward neuroprotection or neurodegeneration in the context of excitotoxic injury. To address this question, we transduced hippocampal slice cultures from 1-week-old C57B/6 mice with recombinant adeno-associated virus carrying an EAAT2 gene expression cassette. EAAT2 gene expression was driven in neurons with the neuron-specific enolase promoter. Using this model system, we were able to induce a significant increase in the expression of functional EAAT2. Consequently, a significant increase in CA1 neuronal damage was observed in slices over-expressing EAAT2 in neurons following an acute exposure to exogenous glutamate. These data suggest that the increased expression of EAAT2 within neurons may contribute to neurodegeneration.

eng

IM

MEDLINE

0953-816X

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NLM

2291-6

pubmed-meshheading:15869527-Amino Acid Transport System X-AG, pubmed-meshheading:15869527-Analysis of Variance, pubmed-meshheading:15869527-Animals, pubmed-meshheading:15869527-Animals, Newborn, pubmed-meshheading:15869527-Aspartic Acid, pubmed-meshheading:15869527-Blotting, Western, pubmed-meshheading:15869527-Cell Death, pubmed-meshheading:15869527-Cells, Cultured, pubmed-meshheading:15869527-Dose-Response Relationship, Drug, pubmed-meshheading:15869527-Enzyme Inhibitors, pubmed-meshheading:15869527-Excitatory Amino Acid Transporter 2, pubmed-meshheading:15869527-Gene Expression, pubmed-meshheading:15869527-Glutamate Plasma Membrane Transport Proteins, pubmed-meshheading:15869527-Glutamic Acid, pubmed-meshheading:15869527-Green Fluorescent Proteins, pubmed-meshheading:15869527-Hippocampus, pubmed-meshheading:15869527-Humans, pubmed-meshheading:15869527-Kainic Acid, pubmed-meshheading:15869527-Mice, pubmed-meshheading:15869527-Neuroglia, pubmed-meshheading:15869527-Organ Culture Techniques, pubmed-meshheading:15869527-Phosphopyruvate Hydratase, pubmed-meshheading:15869527-Pyramidal Cells, pubmed-meshheading:15869527-Symporters, pubmed-meshheading:15869527-Time Factors, pubmed-meshheading:15869527-Transduction, Genetic, pubmed-meshheading:15869527-Tritium

Over-expression of the human EAAT2 glutamate transporter within neurons of mouse organotypic hippocampal slice cultures leads to increased vulnerability of CA1 pyramidal cells.

Journal Article, Comparative Study, In Vitro, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural