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The Journal of Neuroscience, January 12, 2005, 25(2):352-362; doi:10.1523/JNEUROSCI.3887-04.2005

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Cellular/Molecular
Breakdown of Axonal Synaptic Vesicle Precursor Transport by Microglial Nitric Oxide

Massimiliano Stagi,^1,2 Petra S. Dittrich,³ Nadja Frank,¹ Asparouh I. Iliev,¹ Petra Schwille,³ and Harald Neumann^1,2

¹Neuroimmunology Group, European Neuroscience Institute Göttingen, 37073 Göttingen, Germany, ²Institute of Multiple Sclerosis Research, University Göttingen and Hertie-Foundation, 37073 Göttingen, Germany, and ³Experimental Biophysics Group, Max-Planck Institute of Biophysical Chemistry, 37077 Göttingen, Germany

The mechanism of axonal injury in inflammatory brain diseases is still unclear. Increased microglial production of nitric oxide (NO) is a common early sign in neuroinflammatory diseases. We found by fluorescence correlation spectroscopy that synaptophysin tagged with enhanced green fluorescence protein (synaptophysin-EGFP) moves anterogradely in axons of cultured neurons. Activated microglia focally inhibited the axonal movement of synaptophysin-EGFP in a NO synthase-dependent manner. Direct application of a NO donor to neurons resulted in inhibition of axonal transport of synaptophysin-EGFP and synaptotagmin I tagged with EGFP, mediated via phosphorylation of c-jun NH(2)-terminal kinase (JNK). Thus, overt production of reactive NO by activated microglia blocks the axonal transport of synaptic vesicle precursors via phosphorylation of JNK and could cause axonal and synaptic dysfunction.

Key words: axonal transport; axoplasmic transport; immunity; macrophage; microglia; multiple sclerosis; synaptic

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Received Sep 20, 2004; revised November 8, 2004; accepted November 16, 2004.

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