title: Cholesterol deficiency perturbs actin signaling and glutamate homeostasis in hippocampal astrocytes.
abstract: This study was undertaken to explore the possibility that cholesterol deficiency may perturb the physiological functions of astrocytes, thus rendering cells vulnerable to the cytotoxicity induced by glutamate (Glu). Cholesterol deprivation induces astrocyte stellation, which is accompanied by disruption of cortical actin, and phosphorylation of extracellular signal-regulated kinase (ERK) in an astrocyte-specific manner. Moreover, cholesterol reduction decreases the activity of glutamine synthetase (GS) while enhancing the capacity of Glu transporter. Using [(3)H]d-aspartate as a tracer, we found a marked efflux of [(3)H]d-aspartate from cholesterol-deficient astrocytes after Glu stimulation. Changes in the actin cytoskeleton, cell morphology, ERK phosphorylation and GS level gradually recovered in astrocytes after the withdrawal of cholesterol depletion. Moreover, withdrawal of cholesterol deprivation attenuated cell loss in cholesterol-deficient astrocytes during Glu exposure. Taken together, our data suggest that, upon Glu exposure, there would be an increase in intracellular Glu as a consequence of enhanced Glu uptake and reduced degradation of Glu by GS in cholesterol-deficient astrocytes. This in turn leads to a concentration gradient favoring Glu release, thereby causing the accumulation of cytotoxic levels of Glu extracellularly. It is thus concluded that the detrimental effect of cholesterol deprivation may, in part, arise from the impairment in Glu homeostasis.
authors.affiliation: Institute of Neuroscience, School of Life Science, National Yang-Ming University, Taipei, Taiwan, ROC.
authors.forename: Hung-I
authors.initials: HI
authors.lastname: Tsai
authors.forename: Lien-Hsin
authors.initials: LH
authors.lastname: Tsai
authors.forename: Mei-Yun
authors.initials: MY
authors.lastname: Chen
authors.forename: Yun-Chia
authors.initials: YC
authors.lastname: Chou
mesh_terms: D000199:Actins / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001224:Aspartic Acid / Q000493:pharmacokinetics; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D048429:Cell Size; D002478:Cells, Cultured; D002784:Cholesterol / Q000172:deficiency*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D008148:Lovastatin / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014316:Tritium / Q000493:pharmacokinetics; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D000199:Actins; D005904:Glial Fibrillary Acidic Protein; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D047392:beta-Cyclodextrins; D014316:Tritium; D001224:Aspartic Acid; D018698:Glutamic Acid; D002784:Cholesterol; D008148:Lovastatin; C031215:betadex