Inositol hexakisphosphate suppresses excitatory neurotransmission via synaptotagmin-1 C2B domain in the hippocampal neuron

Shao Nian Yang, Yue Shi, Guang Yang, Yuxin Li, Lina Yu, Ok Ho Shin, Taulant Bacaj, Thomas C. Südhof, Jia Yu, Per Olof Berggren

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Inositol hexakisphosphate (InsP6) levels rise and fall with neuronal excitation and silence, respectively, in the hippocampus, suggesting potential signaling functions of this inositol polyphosphate in hippocampal neurons. We now demonstrate that intracellular application of InsP6 caused a concentration-dependent inhibition of autaptic excitatory postsynaptic currents (EPSCs) in cultured hippocampal neurons. The treatment did not alter the size and replenishment rate of the readily releasable pool in autaptic neurons. Intracellular exposure to InsP6 did not affect spontaneous EPSCs or excitatory amino acid-activated currents in neurons lacking autapses. The InsP6-induced inhibition of autaptic EPSCs was effectively abolished by coapplication of an antibody to synaptotagmin-1 C2B domain. Importantly, preabsorption of the antibody with a GST-WT synaptotagmin-1 C2B domain fragment but not with a GST-mutant synaptotagmin-1 C2B domain fragment that poorly reacted with the antibody impaired the activity of the antibody on the InsP6-induced inhibition of autaptic EPSCs. Furthermore, K + depolarization significantly elevated endogenous levels of InsP6 and occluded the inhibition of autaptic EPSCs by exogenous InsP6. These data reveal that InsP6 suppresses excitatory neurotransmission via inhibition of the presynaptic synaptotagmin-1 C2B domain-mediated fusion via an interaction with the synaptotagmin Ca 2+-binding sites rather than via interference with presynaptic Ca2+ levels, synaptic vesicle trafficking, or inactivation of postsynaptic ionotropic glutamate receptors. Therefore, elevated InsP 6 in activated neurons serves as a unique negative feedback signal to control hippocampal excitatory neurotransmission.

Original languageEnglish (US)
Pages (from-to)12183-12188
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number30
DOIs
StatePublished - Jul 24 2012

Keywords

  • Ca sensor
  • Exocytosis
  • Synaptic signal transduction
  • Whole cell patch clamp recording

ASJC Scopus subject areas

  • General

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