A polymorphism in the Crhr1 gene determines stress vulnerability in male mice.
Chronic stress is a risk factor for psychiatric disorders but does not necessarily lead to uniform long-term effects on mental health, suggesting modulating factors such as genetic predispositions. Here we address the question whether natural genetic variations in the mouse CRH receptor 1 (Crhr1) locus modulate the effects of adolescent chronic social stress (ACSS) on long-term stress hormone dysregulation in outbred CD1 mice, which allows a better understanding of the currently reported genes × environment interactions of early trauma and CRHR1 in humans. We identified 2 main haplotype variants in the mouse Crhr1 locus that modulate the long-term effects of ACSS on basal hypothalamic-pituitary-adrenal axis activity. This effect is likely mediated by higher levels of CRHR1, because Crhr1 mRNA expression and CRHR1 binding were enhanced in risk haplotype carriers. Furthermore, a CRHR1 receptor antagonist normalized these long-term effects. Deep sequencing of the Crhr1 locus in CD1 mice revealed a large number of linked single-nucleotide polymorphisms with some located in important regulatory regions, similar to the location of human CRHR1 variants implicated in modulating gene × stress exposure interactions. Our data support that the described gene × stress exposure interaction in this animal model is based on naturally occurring genetic variations in the Crhr1 gene associated with enhanced CRHR1-mediated signaling. Our results suggest that patients with a specific genetic predisposition in the CRHR1 gene together with an exposure to chronic stress may benefit from a treatment selectively antagonizing CRHR1 hyperactivity.
Max Planck Institute of Psychiatry (C.L., C.K., J.H., C.D., A.A, P.W., J.A., C.Q., K.V.W., S.H.S., L.C., R.W-A., J.B., R.L., F.H., M.U., F.H., E.B.B., M.V.S.), 80804 Munich, Germany; Lundbeck Research USA (K.A.J.), Paramus, New Jersey 07652; and Johannes Gutenberg University Medical Center (M.B.M.), 55131 Mainz, Germany.
Christiana
C
Labermaier
Christine
C
Kohl
Jakob
J
Hartmann
Christian
C
Devigny
Andre
A
Altmann
Peter
P
Weber
Janine
J
Arloth
Carina
C
Quast
Klaus V
KV
Wagner
Sebastian H
SH
Scharf
Ludwig
L
Czibere
Regina
R
Widner-Andrä
Julia
J
Brenndörfer
Rainer
R
Landgraf
Felix
F
Hausch
Ken A
KA
Jones
Marianne B
MB
Müller
Manfred
M
Uhr
Florian
F
Holsboer
Elisabeth B
EB
Binder
Mathias V
MV
Schmidt
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive; D003345:Corticosterone / Q000097:blood; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D010902:Pituitary Gland / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011720:Pyrazoles / Q000494:pharmacology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013315:Stress, Psychological / Q000235:genetics*; D014227:Triazines / Q000494:pharmacology; D000099052:CRF Receptor, Type 1
C404928:DMP 696; D011720:Pyrazoles; D018019:Receptors, Corticotropin-Releasing Hormone; D014227:Triazines; D000099052:CRF Receptor, Type 1; D003345:Corticosterone