Regulation of nuclear factor κB in the hippocampus by group I metabotropic glutamate receptors

Kenneth J. O'Riordan, I. Chia Huang, Marina Pizzi, PierFranco Spano, Flora Boroni, Regula Egli, Priyanka Desai, Olivia Fitch, Lauren Malone, Jin Ahn Hyung, Hsiou Chi Liou, J. David Sweatt, Jonathan M. Levenson

Research output: Contribution to journalArticlepeer-review

Abstract

An increasing amount of evidence suggests that the family of nuclear factor κB (NF-κB) transcription factors plays an important role in synaptic plasticity and long-term memory formation. The present study investigated the regulation of NF-αB family members p50, p65/RelA, and c-Rel in the hippocampus in response to metabotropic glutamate receptor (mGluR) signaling. Activation of group I metabotropic glutamate receptors (GpI-mGluRs) with the agonist (S)-3,5-dihydroxyphenylglycine (DHPG) resulted in a time-dependent increase in DNA binding activity of p50, p65, and c-Rel in area CA1 of the hippocampus. An antagonist of mGluR5, 2-Methyl-6-(phenylethynyl) pyridine, inhibited the DHPG-induced activation of NF-κB, whereas an antagonist of mGluR1, (S)-(+)-α-amino-4-carboxy-2-methylbenzeneacetic acid, did not. Using a series of inhibitors, we investigated the signaling pathways necessary for DHPG-induced activation of NF-κB and found that they included the phosphatidyl inositol 3-kinase, protein kinase C, mitogen-activated protein kinase kinase, and p38-mitogen-activated protein kinase pathways. To determine the functional significance of mGluR-induced regulation of NF-κB, we measured long-term depression (LTD) of Schaffer-collateral synapses in the hippocampus of c-Rel knock-out mice. Early phase LTD was normal in c-rel-/- mice. However, late-phase LTD (>90 min) was impaired in c-rel-/- mice. The observations of this deficit in hippocampal synaptic plasticity prompted us to further investigate long-term memory formation in c-rel-/- mice. c-rel-/- mice exhibited impaired performance in a long-term passive avoidance task, providing additional evidence for c-Rel in long-termmemoryformation. These results demonstrate that the NF-κB transcription factor family is regulated by GpI-mGluRs in the hippocampus and that the c-Rel transcription factor is necessary for long-term maintenance of LTD and formation of long-term memory.

Original languageEnglish
Pages (from-to)4870-4879
Number of pages10
JournalJournal of Neuroscience
Volume26
Issue number18
DOIs
Publication statusPublished - 2006

Keywords

  • c-Rel
  • Hippocampus
  • Long-term depression
  • Memory
  • Metabotropic glutamate receptor
  • NF-κB

ASJC Scopus subject areas

  • Neuroscience(all)

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