Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability.
Stress is a major risk factor for numerous neuropsychiatric diseases. However, susceptibility to stress and the qualitative nature of stress effects on behavior differ markedly among individuals. This is partly because of the moderating influence of genetic factors. Inbred mouse strains provide a relatively stable and restricted range of genetic and environmental variability that is valuable for disentangling gene-stress interactions. Here, we screened a panel of inbred strains for anxiety- and depression-related phenotypes at baseline (trait) and after exposure to repeated restraint. Two strains, DBA/2J and C57BL/6J, differed in trait and restraint-induced anxiety-related behavior (dark/light exploration, elevated plus maze). Gene expression analysis of amygdala, medial prefrontal cortex, and hippocampus revealed divergent expression in DBA/2J and C57BL/6J both at baseline and after repeated restraint. Restraint produced strain-dependent expression alterations in various genes including glutamate receptors (e.g., Grin1, Grik1). To elucidate neuronal correlates of these strain differences, we performed ex vivo analysis of glutamate excitatory neurotransmission in amygdala principal neurons. Repeated restraint augmented amygdala excitatory postsynaptic signaling and altered metaplasticity (temporal summation of NMDA receptor currents) in DBA/2J but not C57BL/6J. Furthermore, we found that the C57BL/6J-like changes in anxiety-related behavior after restraint were absent in null mutants lacking the modulatory NMDA receptor subunit Grin2a, but not the AMPA receptor subunit Gria1. Grin2a null mutants exhibited significant ( approximately 30%) loss of dendritic spines on amygdala principal neurons under nonrestraint conditions. Collectively, our data support a model in which genetic variation in glutamatergic neuroplasticity in corticolimbic circuitry underlies phenotypic variation in responsivity to stress.
Mozhui
Khyobeni
K
Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
Karlsson
Rose-Marie
RM
Kash
Thomas L
TL
Ihne
Jessica
J
Norcross
Maxine
M
Patel
Sachin
S
Farrell
Mollee R
MR
Hill
Elizabeth E
EE
Graybeal
Carolyn
C
Martin
Kathryn P
KP
Camp
Marguerite
M
Fitzgerald
Paul J
PJ
Ciobanu
Daniel C
DC
Sprengel
Rolf
R
Mishina
Masayoshi
M
Wellman
Cara L
CL
Winder
Danny G
DG
Williams
Robert W
RW
Holmes
Andrew
A
D000679:Amygdala / Q000503:physiopathology*; D000818:Animals; D049229:Dendritic Spines / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics / Q000502:physiology; D015870:Gene Expression; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D017397:Prefrontal Cortex / Q000503:physiopathology; D018091:Receptors, AMPA / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012149:Restraint, Physical; D013045:Species Specificity; D013315:Stress, Psychological / Q000235:genetics* / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology
D018698:Glutamic Acid; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate
Int J Neuropsychopharmacol. 2008 May;11(3):331-49
17655807
Am J Psychiatry. 2010 May;167(5):509-27
20231323
BMC Genomics. 2007 Mar 16;8:76
17367521
Genes Brain Behav. 2006 Jun;5(4):346-54
16716204
Mol Psychiatry. 2007 Aug;12(8):756-66
17457314
Cereb Cortex. 2009 Oct;19(10):2479-84
19193712
Behav Brain Res. 2004 Nov 5;155(1):135-46
15325787
Biol Psychiatry. 2007 Mar 15;61(6):782-96
17224133
Nat Rev Neurosci. 2006 Feb;7(2):137-51
16429123
Neuron. 2004 Sep 30;44(1):5-21
15450156
Neuron. 2002 Mar 28;34(1):13-25
11931738
J Pharmacol Exp Ther. 2006 Aug;318(2):629-40
16651400
BMC Genomics. 2006 Jun 13;7:146
16772024
Neuropsychopharmacology. 2004 Nov;29(11):2007-17
15266352
PLoS One. 2009;4(1):e4326
19177164
Neurosci Biobehav Rev. 2007;31(1):3-17
16950513
Physiol Behav. 1996 Jul;60(1):129-34
8804652
Nat Genet. 2004 Nov;36(11):1197-202
15489855
Am J Anat. 1970 Apr;127(4):321-55
4985058
Neurosci Biobehav Rev. 2005;29(4-5):525-46
15925696
Neuropsychopharmacology. 2008 Oct;33(11):2595-604
18185497
Pharmacol Ther. 2007 May;114(2):222-32
17395264
Genes Brain Behav. 2005 Jul;4(5):273-88
16011574
Neuropsychopharmacology. 2006 Nov;31(11):2405-14
16482087
Neuron. 2007 Oct 4;56(1):19-32
17920012
J Comp Neurol. 1991 Apr 8;306(2):307-19
1711057
Behav Brain Res. 2006 Nov 25;175(1):43-50
17023061
Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2786-91
11226318
Learn Mem. 2008 Aug 06;15(8):551-64
18685145
Neurosci Biobehav Rev. 2009 Jun;33(6):773-83
19111570
Mol Psychiatry. 2008 Jun;13(6):631-40
17684498
Physiol Behav. 2007 May 16;91(1):77-86
17363014
Cell. 2007 Oct 19;131(2):391-404
17956738
Behav Pharmacol. 2009 Mar;20(2):204-9
18830130
Amino Acids. 2006 Oct;31(3):231-9
16733616
Genes Brain Behav. 2008 Jun;7(4):496-505
18182070
Eur J Pharmacol. 2003 Jan 17;459(2-3):221-30
12524150
Neuron. 2004 Aug 5;43(3):401-13
15294147
Nature. 1977 Apr 21;266(5604):730-2
559941
Neuron. 1996 Sep;17(3):461-74
8816709
Curr Biol. 2001 May 15;11(10):725-34
11378382
Neuron. 2001 Jan;29(1):157-69
11182088
Neuropsychopharmacology. 2009 Oct;34(11):2420-9
19553918
Neuroscience. 2006 Dec 1;143(2):387-93
16962717
J Neurosci. 2007 Jan 17;27(3):684-91
17234600
Learn Mem. 2008 Jan 28;15(2):50-4
18230672
Nature. 1995 Jan 12;373(6510):151-5
7816096
Nature. 2005 Dec 1;438(7068):662-6
16244648
J Neurosci Methods. 1981 Aug;4(2):117-25
6168870
Psychopharmacology (Berl). 2008 Oct;200(3):413-24
18594797
Behav Genet. 2007 Jan;37(1):171-213
17029009
Science. 1999 Jun 11;284(5421):1805-11
10364547
Trends Cogn Sci. 2006 Apr;10(4):182-91
16530463
Pharmacol Biochem Behav. 1981 Nov;15(5):695-9
6118883
Nat Rev Neurosci. 2009 Jun;10(6):423-33
19469026
J Neurosci. 2008 Aug 27;28(35):8709-23
18753372
Behav Brain Res. 2001 Nov 1;125(1-2):141-9
11682105
Science. 2003 Feb 21;299(5610):1240-3
12595695
Methods. 2001 Dec;25(4):402-8
11846609
Nat Rev Drug Discov. 2005 Sep;4(9):775-90
16138108
Genes Brain Behav. 2007 Nov;6(8):736-49
17309658
Behav Brain Res. 2002 Nov 15;136(2):489-501
12429412
Annu Rev Neurosci. 2000;23:155-84
10845062
J Neurosci. 2002 Aug 1;22(15):6810-8
12151561
J Neurosci. 2003 Jun 1;23(11):4667-76
12805306
Psychopharmacology (Berl). 2007 Apr;191(2):311-22
17206494
J Neurosci. 2005 Mar 2;25(9):2255-66
15745951