Inositol 1,4,5-trisphosphate 3-kinase A overexpressed in mouse forebrain modulates synaptic transmission and mGluR-LTD of CA1 pyramidal neurons

PLoS One. 2018 Apr 4;13(4):e0193859. doi: 10.1371/journal.pone.0193859. eCollection 2018.

Abstract

Inositol 1,4,5-trisphosphate 3-kinase A (IP3K-A) regulates the level of the inositol polyphosphates, inositol trisphosphate (IP3) and inositol tetrakisphosphate to modulate cellular signaling and intracellular calcium homeostasis in the central nervous system. IP3K-A binds to F-actin in an activity-dependent manner and accumulates in dendritic spines, where it is involved in the regulation of synaptic plasticity. IP3K-A knockout mice exhibit deficits in some forms of hippocampus-dependent learning and synaptic plasticity, such as long-term potentiation in the dentate gyrus synapses of the hippocampus. In the present study, to further elucidate the role of IP3K-A in the brain, we developed a transgenic (Tg) mouse line in which IP3K-A is conditionally overexpressed approximately 3-fold in the excitatory neurons of forebrain regions, including the hippocampus. The Tg mice showed an increase in both presynaptic release probability of evoked responses, along with bigger synaptic vesicle pools, and miniature excitatory postsynaptic current amplitude, although the spine density or the expression levels of the postsynaptic density-related proteins NR2B, synaptotagmin 1, and PSD-95 were not affected. Hippocampal-dependent learning and memory tasks, including novel object recognition and radial arm maze tasks, were partially impaired in Tg mice. Furthermore, (R,S)-3,5-dihydroxyphenylglycine-induced metabotropic glutamate receptor long-term depression was inhibited in Tg mice and this inhibition was dependent on protein kinase C but not on the IP3 receptor. Long-term potentiation and depression dependent on N-methyl-d-aspartate receptor were marginally affected in Tg mice. In summary, this study shows that overexpressed IP3K-A plays a role in some forms of hippocampus-dependent learning and memory tasks as well as in synaptic transmission and plasticity by regulating both presynaptic and postsynaptic functions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CA1 Region, Hippocampal / cytology*
  • CA1 Region, Hippocampal / physiology
  • Long-Term Synaptic Depression*
  • Male
  • Maze Learning
  • Memory
  • Mice
  • Mice, Transgenic
  • Neuronal Plasticity
  • Phosphotransferases (Alcohol Group Acceptor) / analysis
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Prosencephalon / cytology
  • Prosencephalon / physiology
  • Pyramidal Cells / cytology*
  • Pyramidal Cells / metabolism
  • Receptors, Metabotropic Glutamate / metabolism*
  • Synaptic Transmission*
  • Up-Regulation

Substances

  • Receptors, Metabotropic Glutamate
  • Phosphotransferases (Alcohol Group Acceptor)
  • Inositol 1,4,5-trisphosphate 3-kinase

Grant support

This work was supported by National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT & Future Planning (NRF-2017M3C7A1048566, NRF-2012M3A9B6055378, NRF-2017M3C7A1079692 to H. Kim; NRF-2016M3C7A1905119 to C-H. Kim) and KIST Institutional Program (2E28412 to C-H. Kim).