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Impaired PtdIns(4,5)P2 synthesis in nerve terminals produces defects in synaptic vesicle trafficking

Author

Listed:
  • Gilbert Di Paolo

    (Yale University School of Medicine
    Yale University School of Medicine)

  • Howard S. Moskowitz

    (Weill Medical College of Cornell University)

  • Keith Gipson

    (Yale University School of Medicine)

  • Markus R. Wenk

    (Yale University School of Medicine
    Yale University School of Medicine)

  • Sergey Voronov

    (Yale University School of Medicine
    Yale University School of Medicine)

  • Masanori Obayashi

    (Yale University School of Medicine
    Yale University School of Medicine)

  • Richard Flavell

    (Yale University School of Medicine
    Yale University School of Medicine)

  • Reiko M. Fitzsimonds

    (Yale University School of Medicine)

  • Timothy A. Ryan

    (Weill Medical College of Cornell University)

  • Pietro De Camilli

    (Yale University School of Medicine
    Yale University School of Medicine)

Abstract

Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) has an important function in cell regulation both as a precursor of second messenger molecules and by means of its direct interactions with cytosolic and membrane proteins. Biochemical studies have suggested a role for PtdIns(4,5)P2 in clathrin coat dynamics, and defects in its dephosphorylation at the synapse produce an accumulation of coated endocytic intermediates. However, the involvement of PtdIns(4,5)P2 in synaptic vesicle exocytosis remains unclear. Here, we show that decreased levels of PtdIns(4,5)P2 in the brain and an impairment of its depolarization-dependent synthesis in nerve terminals lead to early postnatal lethality and synaptic defects in mice. These include decreased frequency of miniature currents, enhanced synaptic depression, a smaller readily releasable pool of vesicles, delayed endocytosis and slower recycling kinetics. Our results demonstrate a critical role for PtdIns(4,5)P2 synthesis in the regulation of multiple steps of the synaptic vesicle cycle.

Suggested Citation

  • Gilbert Di Paolo & Howard S. Moskowitz & Keith Gipson & Markus R. Wenk & Sergey Voronov & Masanori Obayashi & Richard Flavell & Reiko M. Fitzsimonds & Timothy A. Ryan & Pietro De Camilli, 2004. "Impaired PtdIns(4,5)P2 synthesis in nerve terminals produces defects in synaptic vesicle trafficking," Nature, Nature, vol. 431(7007), pages 415-422, September.
    • Handle: RePEc:nat:nature:v:431:y:2004:i:7007:d:10.1038_nature02896
    DOI: 10.1038/nature02896
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