title: Enhanced asynchronous Ca(2+) oscillations associated with impaired glutamate transport in cortical astrocytes expressing Fmr1 gene premutation expansion.
abstract: BACKGROUND
  FMR1 CGG expansion repeats in the premutation range have not been linked to astrocyte pathophysiology.
  
  
  RESULTS
  Premutation cortical astrocytes display decreased Glu transporter expression/activity and enhanced asynchronous Ca(2+) oscillations.
  
  
  CONCLUSIONS
  Glu transport and Ca(2+) signaling defects in premutation astrocytes could contribute to FXTAS neuropathology.
  
  
  CONCLUSIONS
  Premutation astrocytes may have an etiological role in FXTAS neuropathology. Premutation CGG repeat expansions (55-200 CGG repeats; preCGG) within the fragile X mental retardation 1 (FMR1) gene can cause fragile X-associated tremor/ataxia syndrome. Defects in early neuronal migration and morphology, electrophysiological activity, and mitochondria trafficking have been described in a premutation mouse model, but whether preCGG mutations also affect astrocyte function remains unknown. PreCGG cortical astrocytes (∼170 CGG repeats) displayed 3-fold higher Fmr1 mRNA and 30% lower FMR1 protein (FMRP) when compared with WT. PreCGG astrocytes showed modest reductions in expression of glutamate (Glu) transporters GLT-1 and GLAST and attenuated Glu uptake (p < 0.01). Consistent with astrocyte cultures in vitro, aged preCGG mice cerebral cortex also displayed reduced GLAST and GLT-1 expression. Approximately 65% of the WT and preCGG cortical astrocytes displayed spontaneous asynchronous Ca(2+) oscillations. PreCGG astrocytes exhibited nearly 50% higher frequency of asynchronous Ca(2+) oscillations (p < 0.01) than WT, a difference mimicked by chronic exposure of WT astrocytes to l-trans-pyrrolidine-2,4-dicarboxylic acid (l-trans-PDC) or by partial suppression of GLAST using siRNA interference. Acute challenge with Glu augmented the frequency of Ca(2+) oscillations in both genotypes. Additionally, 10 μm Glu elicited a sustained intracellular Ca(2+) rise in a higher portion of preCGG astrocytes when compared with WT. Pharmacological studies showed that mGluR5, but not NMDA receptor, contributed to Glu hypersensitivity in preCGG astrocytes. These functional defects in preCGG astrocytes, especially in Glu signaling, may contribute to fragile X-associated tremor/ataxia syndrome neuropathology.
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University ofCalifornia, Davis, California 95616, USA. zcao@ucdavis.edu
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Cao
authors.forename: Susan
authors.initials: S
authors.lastname: Hulsizer
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Cui
authors.forename: Dalyir L
authors.initials: DL
authors.lastname: Pretto
authors.forename: Kyung Ho
authors.initials: KH
authors.lastname: Kim
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hagerman
authors.forename: Flora
authors.initials: F
authors.lastname: Tassone
authors.forename: Isaac N
authors.initials: IN
authors.lastname: Pessah
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001259:Ataxia / Q000235:genetics; D001692:Biological Transport; D020013:Calcium Signaling; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology; D003998:Dicarboxylic Acids / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism* / Q000502:physiology; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000494:pharmacology; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D017470:Receptors, Glutamate / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D014202:Tremor / Q000235:genetics; D019680:Trinucleotide Repeat Expansion
chemical_list: D003998:Dicarboxylic Acids; D018690:Excitatory Amino Acid Agonists; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D051860:Fragile X Messenger Ribonucleoprotein 1; D018698:Glutamic Acid; D016202:N-Methylaspartate; D014179:Neurotransmitter Uptake Inhibitors; D011759:Pyrrolidines; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; C497684:Fmr1 protein, mouse; C493393:Slc1a3 protein, mouse; C083486:pyrrolidine-2,4-dicarboxylic acid
keywords: Astrocytes; Ca2+ Oscillation; Calcium; FXTAS; Glutamate Transporter; Neurodegenerative Diseases; Neurological Diseases; Neurotransmitter Transport; Premutation CGG Expansion
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