title: The immediate early gene early growth response gene 3 mediates adaptation to stress and novelty.
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.
authors: Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, Box 8134, St. Louis, MO 63110, USA. amelia@email.arizona.edu
authors: A
authors: A
authors: Gallitano-Mendel
authors: Y
authors: Y
authors: Izumi
authors: K
authors: K
authors: Tokuda
authors: C F
authors: CF
authors: Zorumski
authors: M P
authors: MP
authors: Howell
authors: L J
authors: LJ
authors: Muglia
authors: D F
authors: DF
authors: Wozniak
authors: J
authors: J
authors: Milbrandt
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D003345:Corticosterone / Q000378:metabolism; D051776:Early Growth Response Protein 3 / Q000235:genetics*; D005106:Exploratory Behavior / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D017781:Genes, Immediate-Early / Q000235:genetics; D006185:Habituation, Psychophysiologic / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D007859:Learning Disabilities / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D017774:Long-Term Potentiation / Q000235:genetics; D036881:Long-Term Synaptic Depression / Q000235:genetics; D008297:Male; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D013315:Stress, Psychological / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology
chemical_list: C497369:Egr3 protein, mouse; C121001:NR2B NMDA receptor; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D051776:Early Growth Response Protein 3; D003345:Corticosterone
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