Endosomal phosphatidylinositol 3-phosphate controls synaptic vesicle cycling and neurotransmission

Guan Ting Liu, Gaga Kochlamazashvili, Dmytro Puchkov, Rainer Müller, Carsten Schultz, Albert I. Mackintosh, Dennis Vollweiter, Volker Haucke, Tolga Soykan

Research output: Contribution to journalArticlepeer-review

Abstract

Neural circuit function requires mechanisms for controlling neurotransmitter release and the activity of neuronal networks, including modulation by synaptic contacts, synaptic plasticity, and homeostatic scaling. However, how neurons intrinsically monitor and feedback control presynaptic neurotransmitter release and synaptic vesicle (SV) recycling to restrict neuronal network activity remains poorly understood at the molecular level. Here, we investigated the reciprocal interplay between neuronal endosomes, organelles of central importance for the function of synapses, and synaptic activity. We show that elevated neuronal activity represses the synthesis of endosomal lipid phosphatidylinositol 3-phosphate [PI(3)P] by the lipid kinase VPS34. Neuronal activity in turn is regulated by endosomal PI(3)P, the depletion of which reduces neurotransmission as a consequence of perturbed SV endocytosis. We find that this mechanism involves Calpain 2-mediated hyperactivation of Cdk5 downstream of receptor- and activity-dependent calcium influx. Our results unravel an unexpected function for PI(3)P-containing neuronal endosomes in the control of presynaptic vesicle cycling and neurotransmission, which may explain the involvement of the PI(3)P-producing VPS34 kinase in neurological disease and neurodegeneration.

Original languageEnglish (US)
Article numbere109352
JournalEMBO Journal
Volume41
Issue number9
DOIs
StatePublished - May 2 2022
Externally publishedYes

Keywords

  • endocytosis
  • endosomes
  • neurotransmission
  • phosphatidylinositol 3-phosphate
  • synaptic vesicle

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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