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Retrograde regulation of synaptic vesicle endocytosis and recycling

Nature Neuroscience volume 6, pages 925–932 (2003)Cite this article

Abstract

Sustained release of neurotransmitter depends upon the recycling of synaptic vesicles. Until now, it has been assumed that vesicle recycling is regulated by signals from the presynaptic bouton alone, but results from rat hippocampal neurons reported here indicate that this need not be the case. Fluorescence imaging and pharmacological analysis show that a nitric oxide (NO) signal generated postsynaptically can regulate endocytosis and at least one later step in synaptic vesicle recycling. The proposed retrograde pathway involves an NMDA receptor (NMDAR)-dependent postsynaptic production of NO, diffusion of NO to a presynaptic site, and a cGMP-dependent increase in presynaptic phosphatidylinositol 4,5-biphosphate (PIP2). These results indicate that the regulation of synaptic vesicle recycling may integrate a much broader range of neural activity signals than previously recognized, including postsynaptic depolarization and the activation of NMDARs at both immediate and nearby postsynaptic active zones.

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Figure 1: Retrograde regulation of endocytosis.
Figure 2: Cyclic GMP production within presynaptic boutons upon electrical stimulation.
Figure 3: Reduction of PIP2 availability results in slower endocytosis.
Figure 4: Effect of scavenging PIP2 by PH–GFP on FM 4-64 unloading.
Figure 5: The effects of reducing PIP2 availability and blocking NO signaling are not additive.
Figure 6: ImmunoEM of hippocampal neuronal cultures showing the ultrastructural distribution of PH–GFP as detected with a monoclonal antibody against GFP.

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Acknowledgements

We thank R.W. Aldrich and the members of the Smith lab for critical reading of the manuscript and Y. Gedde for technical assistance. This work was supported by grants from the US National Institutes of Health and a gift from the Vincent Coates Foundation.

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Authors and Affiliations

  1. Department of Molecular and Cellular Physiology, Stanford University, Stanford, 94305, California, USA

    Kristina D Micheva, JoAnn Buchanan & Stephen J Smith

  2. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, 48109, Michigan, USA

    Ronald W Holz

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Correspondence to Kristina D Micheva.

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Micheva, K., Buchanan, J., Holz, R. et al. Retrograde regulation of synaptic vesicle endocytosis and recycling. Nat Neurosci 6, 925–932 (2003). https://doi.org/10.1038/nn1114

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