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The Journal of Neuroscience, February 8, 2006, 26(6):1730-1738; doi:10.1523/JNEUROSCI.0702-05.2006

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Cellular/Molecular
A Novel Role for Sema3A in Neuroprotection from Injury Mediated by Activated Microglia

Henry H. Majed,^1 * Siddharthan Chandran,^1 * Simone P. Niclou,² Richard S. Nicholas,¹ Alastair Wilkins,¹ Mark G. Wing,¹ Kate E. Rhodes,¹ Maria Grazia Spillantini,¹ and Alastair Compston¹

¹Department of Clinical Neurosciences and Centre for Brain Repair, University of Cambridge, Forvie Site, Cambridge CB2 2PY, United Kingdom, and ²Graduate School of Neurosciences Amsterdam, Netherlands Institute for Brain Research, 1105 AZ Amsterdam, The Netherlands

Correspondence should be addressed to Dr. Alastair Compston, Department of Clinical Neurosciences and Centre for Brain Repair, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 2PY, UK. Email: alastair.compston{at}medschl.cam.ac.uk

Microglia exist under physiological conditions in a resting state but become activated after neuronal injury. Recent studies have highlighted the reciprocal role of neurons in controlling both the number and activity of microglia. In this study, microglia derived from newborn rat cortices were cultured and activated by interferon- (IFN) treatment, then exposed to recombinant Sema3A or conditioned medium derived from stressed embryonic cortical neurons. We found that activation of microglia by IFN induced differential upregulation of the semaphorin receptors Plexin-A1 and Neuropilin-1. This result was confirmed by Northern blotting, reverse transcription-PCR, and Western blotting. Furthermore, recombinant Sema3A induced apoptosis of microglia when added to the in vitro culture, and a similar result was obtained on activated microglia when Sema3A was produced by stressed neurons. Using an in vivo model of microglia activation by striatal injection of lipopolysaccharide demonstrated a corresponding upregulation of Plexin-A1 and Neuropilin-1 in activated microglia and enhanced production of Sema3A by stressed adult neurons. These results suggest a novel semaphorin-mediated mechanism of neuroprotection whereby stressed neurons can protect themselves from further damage by activated microglia.

Key words: microglia; neuron; semaphorin; plexin; neuropilin; neuroprotection

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Received May 31, 2004; revised Nov. 11, 2005; accepted Nov. 14, 2005.

Correspondence should be addressed to Dr. Alastair Compston, Department of Clinical Neurosciences and Centre for Brain Repair, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 2PY, UK. Email: alastair.compston{at}medschl.cam.ac.uk

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