The immediate early gene early growth response gene 3 mediates adaptation to stress and novelty.
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.
Gallitano-Mendel
A
A
Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, Box 8134, St. Louis, MO 63110, USA. amelia@email.arizona.edu
Izumi
Y
Y
Tokuda
K
K
Zorumski
C F
CF
Howell
M P
MP
Muglia
L J
LJ
Wozniak
D F
DF
Milbrandt
J
J
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
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
J Neurosci. 2000 May 15;20(10):3926-35
10804232
Brain Res Mol Brain Res. 1994 Jun;23(4):349-53
8090075
Nat Genet. 2000 Jul;25(3):284-8
10888874
Neuroscience. 2000;99(1):7-16
10924947
Brain Res. 2000 Sep 22;877(2):203-8
10986333
Nat Neurosci. 2001 Mar;4(3):289-96
11224546
Neuron. 2001 May;30(2):355-68
11394999
Exp Neurol. 2001 Aug;170(2):326-44
11476599
Cell. 2001 Nov 30;107(5):617-29
11733061
Neurosci Biobehav Rev. 2002 Jan;26(1):91-104
11835987
Stress. 2002 Feb;5(1):3-13
12171762
Eur J Neurosci. 2002 Sep;16(5):970-4
12372034
Science. 2002 Oct 25;298(5594):776-80
12399578
Hippocampus. 2002;12(5):570-7
12440572
Stress. 2003 Jun;6(2):121-5
12775331
Neurosci Res. 2003 Aug;46(4):415-21
12871763
Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8987-92
12851457
Genes Brain Behav. 2003 Apr;2(2):71-9
12884964
EMBO J. 2003 Aug 15;22(16):4166-77
12912915
Neuron. 2003 Nov 13;40(4):695-701
14622575
Science. 2004 May 14;304(5673):1021-4
15143284
Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):10049-53
7937835
Mol Pharmacol. 1995 Nov;48(5):841-8
7476914
Proc Natl Acad Sci U S A. 1996 May 14;93(10):4750-3
8643474
Curr Opin Neurobiol. 1996 Apr;6(2):187-95
8725960
Nature. 1997 May 29;387(6632):497-500
9168111
Neurosci Res. 1997 Nov;29(3):183-207
9436645
Mol Cell Biol. 1998 Jul;18(7):3744-51
9632757
Brain Res. 1998 Jun 15;796(1-2):132-42
9689463
Nat Genet. 1998 Sep;20(1):87-91
9731539
Brain Res Brain Res Rev. 1998 Dec;28(3):370-490
9858769
Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8739-44
10411945
Learn Mem. 1994 Jul-Aug;1(2):140-52
10467592
J Neurosci. 2004 Dec 8;24(49):11029-34
15590919
J Pain. 2005 Jan;6(1):12-20
15629414
Proc Natl Acad Sci U S A. 2005 Jan 11;102(2):473-8
15623560
J Neurosci. 2005 Feb 16;25(7):1761-8
15716412
Nat Neurosci. 2005 Jun;8(6):759-67
15880109
J Neurosci. 2005 Jul 20;25(29):6907-10
16033900
J Neurosci. 2005 Sep 14;25(37):8386-90
16162920
Neuroscience. 2005;136(1):269-79
16181739
Mol Cell Biol. 2005 Dec;25(23):10286-300
16287845
Neuroscience. 2005;136(2):509-17
16216426
Proc Natl Acad Sci U S A. 2004 May 25;101(21):8192-7
15150407
Ann N Y Acad Sci. 2004 Jun;1018:370-7
15240392
Psychopharmacologia. 1975 Oct 14;44(1):53-9
1197580
Psychopharmacology (Berl). 1982;78(4):346-52
6818597
Neuroscience. 1989;32(3):685-700
2689907
Mol Pharmacol. 1993 Oct;44(4):851-9
7901753
Eur J Neurosci. 2006 Jan;23(1):261-72
16420435
Neuron. 2006 Apr 6;50(1):127-43
16600861
J Neurosci. 2006 Jul 5;26(27):7181-8
16822975
Neuron. 2006 Nov 9;52(3):403-7
17088207
Neuron. 2006 Nov 9;52(3):437-44
17088210
Neuron. 2006 Nov 9;52(3):445-59
17088211
Neuron. 2006 Nov 9;52(3):461-74
17088212
Neuropharmacology. 2007 Jan;52(1):71-6
16899258
Neuropharmacology. 2007 Jan;52(1):60-70
16904707
Nat Neurosci. 2005 May;8(5):664-72
15834420
J Neurosci. 2000 Jul 1;20(13):4809-20
10864938