Enhanced Ca2+-dependent glutamate release from astrocytes of the BACHD Huntington's disease mouse model

NEUROBIOLOGY OF DISEASE

卷:58

Article

Lee, William¹  Reyes, Reno C.¹  Gottipati, Manoj K.¹  Lewis, Karon²  Lesort, Mathieu³  Parpura, Vladimir^1,4  Gray, Michelle² 

[1] Univ Alabama Birmingham, Dept Neurobiol, Birmingham, AL 35294 USA

[2] Univ Alabama Birmingham, Dept Neurol, Ctr Neurodegenerat & Expt Therapeut, Birmingham, AL 35294 USA

[3] Univ Alabama Birmingham, Dept Psychiat & Behav Neurobiol, Birmingham, AL 35294 USA

[4] Univ Rijeka, Dept Biotechnol, Rijeka 51000, Croatia

关键词: Huntington's disease;    Astrocytes;    Glutamate;    Pyruvate carboxylase;   

DOI  :  10.1016/j.nbd.2013.06.002

来源: Elsevier

【 摘 要 】

Huntington's disease (HD) causes preferential loss of a subset of neurons in the brain although the huntingtin protein is expressed broadly in various neural cell types, including astrocytes. Glutamate-mediated excitotoxicity is thought to cause selective neuronal injury, and brain astrocytes have a central role in regulating extracellular glutamate. To determine whether full-length mutant huntingtin expression causes a cell-autonomous phenotype and perturbs astrocyte gliotransmitter release, we studied cultured cortical astrocytes from BACHD mice. Here, we report augmented glutamate release through Ca2+-dependent exocytosis from BACHD astrocytes. Although such release is usually dependent on cytosolic Ca2+ levels, surprisingly, we found that BACHD astrocytes displayed Ca2+ dynamics comparable to those in wild type astrocytes. These results point to a possible involvement of other factors in regulating Ca2+-dependent/vesicular release of glutamate from astrocytes. We found a biochemical footprint that would lead to increased availability of cytosolic glutamate in BACHD astrocytes: i) augmented de novo glutamate synthesis due to an increase in the level of the astrocyte specific mitochondrial enzyme pyruvate carboxylase; and ii) unaltered conversion of glutamate to glutamine, as there were no changes in the expression level of the astrocyte specific enzyme glutamine synthetase. This work identifies a new mechanism in astrocytes that could lead to increased levels of extracellular glutamate in HD and thus may contribute to excitotoxicity in this devastating disease. (C) 2013 Elsevier Inc. All rights reserved.

【 授权许可】

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