Stress induced changes in cortical and hypothalamic c-fos expression are altered in fragile X mutant mice.
Fragile X (FraX) syndrome is characterized by mental retardation and a behavioral phenotype that includes stress-related behaviors. Recently, FraX children were shown to have elevated glucocorticoid hormones under basal conditions and an exaggerated hormonal response to stress. In the present study, fragile X mental retardation 1-knockout (Fmr1-KO) and wild-type (WT) mice were subjected to immobilization stress for 30 min or 2 h, killed with paired controls, and the hippocampus, neocortex, and hypothalamic paraventricular nucleus (PVN) assessed by in situ hybridization for effects on c-fos mRNA. The main effect of stress in hippocampus was a reduction in mRNA levels within CA3-CA1 pyramidal cells in both genotypes. Stress significantly reduced CA1 c-fos mRNA in Fmr1-KOs at 30 min (-41%) and 2 h (-57%), whereas in WTs levels were significantly reduced only at 2 h (-57%). In neocortex, 30 min stress significantly increased c-fos mRNA in Fmr1-KOs only (+53%); however, by 2 h levels were reduced in both genotypes versus respective controls. In the paraventricular nucleus, c-fos mRNA levels were significantly, and equally, increased in both genotypes at 30 min. However, at 2 h, mRNA levels were still elevated in the Fmr1-KOs, whereas they had returned to control values in the WTs. Finally, immobilization stress significantly increased serum corticosterone levels in both genotypes at 30 min and 2 h, with Fmr1-KOs exhibiting greater levels than WTs; levels were statistically different at 2 h. These data indicate a greater response to stress in FraX mutants than in WTs, and further support the hypothesis of a dysregulated hypothalamic-pituitary-adrenal (HPA) axis in FraX syndrome.
Lauterborn
Julie C
JC
Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697-4292, USA. jclauter@uci.edu
D000818:Animals; D003345:Corticosterone / Q000097:blood; D051860:Fragile X Messenger Ribonucleoprotein 1; D005600:Fragile X Syndrome / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019579:Neocortex / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010286:Paraventricular Hypothalamic Nucleus / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D016601:RNA-Binding Proteins / Q000235:genetics*; D013312:Stress, Physiological / Q000503:physiopathology*
D003345:Corticosterone; D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C497684:Fmr1 protein, mouse