Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 30, Pages 12183-12188Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1115070109
Keywords
Ca2+ sensor; exocytosis; synaptic signal transduction; whole cell patch clamp recording
Categories
Funding
- Berth von Kantzow's Foundation, EuroDia [FP6-518153]
- European Foundation for the Study of Diabetes
- Family Erling-Persson Foundation
- Fredrik and Ingrid Thuring's Foundation
- Karolinska Institutet
- Knut and Alice Wallenberg Foundation
- Magnus Bergvall's Foundation
- Novo Nordisk Foundation
- Skandia Insurance Company
- Stichting af Jochnick Foundation
- Strategic Research Program in Diabetes at Karolinska Institutet
- Swedish Alzheimer Association
- Swedish Diabetes Association
- Swedish Foundation for Strategic Research
- Swedish Research Council
- Swedish Society of Medicine
- Torsten and Ragnar Soderberg Foundation
- Applied Nano Technology [FP7-228933-2]
- Ake Wiberg's Foundation
- Novo Nordisk Fonden [NNF11OC1014706, NNF12OC1016557] Funding Source: researchfish
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Inositol hexakisphosphate (InsP(6)) 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 InsP(6) 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 InsP(6) did not affect spontaneous EPSCs or excitatory amino acid-activated currents in neurons lacking autapses. The InsP(6)-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 InsP(6)-induced inhibition of autaptic EPSCs. Furthermore, K+ depolarization significantly elevated endogenous levels of InsP(6) and occluded the inhibition of autaptic EPSCs by exogenous InsP(6). These data reveal that InsP(6) suppresses excitatory neurotransmission via inhibition of the presynaptic synaptotagmin-1 C2B domain-mediated fusion via an interaction with the synaptotagmin Ca2+-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.
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