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The Journal of Neuroscience, April 11, 2007, 27(15):3946-3955; doi:10.1523/JNEUROSCI.5030-06.2007

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Neurobiology of Disease
Hypoxia Suppresses Glutamate Transport in Astrocytes

Mark Dallas,¹ Hannah E. Boycott,¹ Lucy Atkinson,² Alison Miller,¹ John P. Boyle,¹ Hugh A. Pearson,² and Chris Peers¹

Schools of ¹Medicine and ²Biomedical Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom

Correspondence should be addressed to Prof. Chris Peers, School of Medicine, University of Leeds, Worsley Building, Leeds LS2 9JT, UK. Email: c.s.peers{at}leeds.ac.uk

Glutamate uptake by astrocytes is fundamentally important in the regulation of CNS function. Disruption of uptake can lead to excitotoxicity and is implicated in various neurodegenerative processes as well as a consequence of hypoxic/ischemic events. Here, we investigate the effect of hypoxia on activity and expression of the key glutamate transporters excitatory amino acid transporter 1 (EAAT1) [GLAST (glutamate-aspartate transporter)] and EAAT2 [GLT-1 (glutamate transporter 1)]. Electrogenic, Na⁺-dependent glutamate uptake was monitored via whole-cell patch-clamp recordings from cortical astrocytes. Under hypoxic conditions (2.5 and 1% O₂ exposure for 24 h), glutamate uptake was significantly reduced, and pharmacological separation of uptake transporter subtypes suggested that the EAAT2 subtype was preferentially reduced relative to the EAAT1. This suppression was confirmed at the level of EAAT protein expression (via Western blots) and mRNA levels (via real-time PCR). These effects of hypoxia to inhibit glutamate uptake current and EAAT protein levels were not replicated by desferrioxamine, cobalt, FG0041, or FG4496, agents known to mimic effects of hypoxia mediated via the transcriptional regulator, hypoxia-inducible factor (HIF). Furthermore, the effects of hypoxia were not prevented by topotecan, which prevents HIF accumulation. In stark contrast, inhibition of nuclear factor-B (NF-B) with SN50 fully prevented the effects of hypoxia on glutamate uptake and EAAT expression. Our results indicate that prolonged hypoxia can suppress glutamate uptake in astrocytes and that this effect requires activation of NF-B but not of HIF. Suppression of glutamate uptake via this mechanism may be an important contributory factor in hypoxic/ischemic triggered glutamate excitotoxicity.

Key words: glia; glutamate transport; hypoxia; patch clamp; astrocyte; transcription

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Received July 5, 2006; revised Feb. 26, 2007; accepted Feb. 28, 2007.

Correspondence should be addressed to Prof. Chris Peers, School of Medicine, University of Leeds, Worsley Building, Leeds LS2 9JT, UK. Email: c.s.peers{at}leeds.ac.uk

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