title: AKT/GSK-3beta/beta-catenin signalling within hippocampus and amygdala reflects genetically determined differences in posttraumatic stress disorder like symptoms.
abstract: Only a small percentage of individuals develop posttraumatic stress disorder (PTSD) in the aftermath of a trauma. It is still largely unknown to what extent gene-environment interactions contribute to the inter-individual differences in PTSD susceptibility and resilience and what cellular processes may underlie long-term maintenance of the disorder. Here we employed a mouse model of PTSD to unravel the contribution of genetic background and maternal influences on long-lasting changes in kinase and transcription factor activities in PTSD-susceptible C57BL/6NCrl (B6N) and resilient C57BL/6JOlaHsd (B6JOla) mice. Mice received an inescapable foot shock and were tested for activity changes in the AKT/GSK-3beta/beta-catenin-pathway in specific brain structures 42 days later. To control for prenatal and postnatal environmental (i.e. maternal) factors part of the experiments were performed with animals originating from within-strain and between-strain embryo transfers. In PTSD-susceptible B6N mice, long-term maintenance of contextual and sensitized fear was accompanied by (i) increased levels of phosphorylated AKT within the dorsal hippocampus and (ii) higher levels of phosphorylated AKT and GSK-3beta and increased beta-catenin levels within the basolateral amygdala. In animals originating from embryo transfers, levels of phosphorylated GSK-3beta and of beta-catenin were decreased in the dorsal hippocampus, but increased in the basolateral amygdala of shocked B6N mice compared to shocked B6JOla mice. This was independent of the genotype of the recipient mothers. At the behavioural level, these differences coincided with sustained sensitized and more pronounced contextual fear of B6N compared to B6JOla mice. Taken together our study identifies lasting changes in the AKT/GSK-3beta/beta-catenin cascade within the hippocampus and amygdala as molecular correlates of genetically determined differences in the severity of PTSD-like symptoms.
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, D-80804 Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Dahlhoff
authors.forename: A
authors.initials: A
authors.lastname: Siegmund
authors.forename: Y
authors.initials: Y
authors.lastname: Golub
authors.forename: E
authors.initials: E
authors.lastname: Wolf
authors.forename: F
authors.initials: F
authors.lastname: Holsboer
authors.forename: C T
authors.initials: CT
authors.lastname: Wotjak
mesh_terms: D000679:Amygdala / Q000378:metabolism*; D000818:Animals; D004624:Embryo Transfer; D005239:Fear; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction; D013045:Species Specificity; D013313:Stress Disorders, Post-Traumatic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D051176:beta Catenin / Q000502:physiology*
chemical_list: D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3