The immediate early gene early growth response gene 3 mediates adaptation to stress and novelty

A. Gallitano-Mendel, Y. Izumi, K. Tokuda, C. F. Zorumski, M. P. Howell, L. J. Muglia, D. F. Wozniak, J. Milbrandt

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Stress and exploration of novel environments induce neural expression of immediate early gene transcription factors (IEG-TFs). However, as yet no IEG-TF has been shown to be required for the normal biological or behavioral responses to these stimuli. Here we show that mice deficient for the IEG-TF early growth response gene (Egr) 3, display accentuated behavioral responses to the mild stress of handling paralleled by increased release of the stress hormone corticosterone. Egr3-/- mice also display abnormal responses to novelty, including heightened reactivity to novel environments and failure to habituate to social cues or startling acoustic stimuli. In a Y-maze spontaneous alternation task, they perform fewer sequential arm entries than controls, suggesting defects in immediate memory. Because stress and novelty stimulate hippocampal long-term depression (LTD), and because abnormalities in habituation to novelty and Y-maze performance have been associated with LTD deficits, we examined this form of synaptic plasticity in Egr3-/- mice. We found that Egr3-/- mice fail to establish hippocampal LTD in response to low frequency stimulation and exhibit dysfunction of an ifenprodil-sensitive (NR1/NR2B) N-methyl-d-aspartate receptor subclass. Long term potentiation induction was not altered. The NR2B-dependent dysfunction does not result from transcriptional regulation of this subunit by Egr3, because NR2B mRNA levels did not differ in the hippocampi of Egr3-/- and control mice. These findings are the first demonstration of the requirement for an IEG-TF in mediating the response to stress and novelty, and in the establishment of LTD.

Original languageEnglish (US)
Pages (from-to)633-643
Number of pages11
JournalNeuroscience
Volume148
Issue number3
DOIs
StatePublished - Sep 7 2007

Keywords

  • LTD
  • LTP
  • corticosterone
  • immediate early gene
  • stress

ASJC Scopus subject areas

  • Neuroscience(all)

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