title: Enhanced Ca(2+)-dependent glutamate release from astrocytes of the BACHD Huntington's disease mouse model.
abstract: 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 Ca(2+)-dependent exocytosis from BACHD astrocytes. Although such release is usually dependent on cytosolic Ca(2+) levels, surprisingly, we found that BACHD astrocytes displayed Ca(2+) dynamics comparable to those in wild type astrocytes. These results point to a possible involvement of other factors in regulating Ca(2+)-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.
authors.affiliation: Department of Neurobiology, University of Alabama, Birmingham, AL 35294, USA.
authors.forename: William
authors.initials: W
authors.lastname: Lee
authors.forename: Reno C
authors.initials: RC
authors.lastname: Reyes
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Gottipati
authors.forename: Karon
authors.initials: K
authors.lastname: Lewis
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lesort
authors.forename: Vladimir
authors.initials: V
authors.lastname: Parpura
authors.forename: Michelle
authors.initials: M
authors.lastname: Gray
mesh_terms: D026922:Amino Acid Transport Systems, Acidic / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology*; D051379:Mice; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010812:Physical Stimulation; D011766:Pyruvate Carboxylase / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D014162:Transfection
chemical_list: D026922:Amino Acid Transport Systems, Acidic; D002118:Calcium; D005904:Glial Fibrillary Acidic Protein; D018698:Glutamic Acid; D049452:Green Fluorescent Proteins; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011766:Pyruvate Carboxylase; C506812:Htt protein, mouse; C485184:enhanced green fluorescent protein; C504941:Slc17a8 protein, mouse
keywords: Astrocytes; Glutamate; Huntington's disease; Pyruvate carboxylase