Long-Lasting Hippocampal Synaptic Protein Loss in a Mouse Model of Posttraumatic Stress Disorder

Abstract

Despite intensive research efforts, the molecular pathogenesis of posttraumatic stress disorder (PTSD) and especially of the hippocampal volume loss found in the majority of patients suffering from this anxiety disease still remains elusive. We demonstrated before that trauma-induced hippocampal shrinkage can also be observed in mice exhibiting a PTSD-like syndrome. Aiming to decipher the molecular correlates of these trans-species posttraumatic hippocampal alterations, we compared the expression levels of a set of neurostructural marker proteins between traumatized and control mice at different time points after their subjection to either an electric footshock or mock treatment which was followed by stressful re-exposure in several experimental groups. To our knowledge, this is the first systematic in vivo study analyzing the long-term neuromolecular sequelae of acute traumatic stress combined with re-exposure. We show here that a PTSD-like syndrome in mice is accompanied by a long-lasting reduction of hippocampal synaptic proteins which interestingly correlates with the strength of the generalized and conditioned fear response but not with the intensity of hyperarousal symptoms. Furthermore, we demonstrate that treatment with the serotonin reuptake inhibitor (SSRI) fluoxetine is able to counteract both the PTSD-like syndrome and the posttraumatic synaptic protein loss. Taken together, this study demonstrates for the first time that a loss of hippocampal synaptic proteins is associated with a PTSD-like syndrome in mice. Further studies will have to reveal whether these findings are transferable to PTSD patients.

Therapeutic Action of Fluoxetine is Associated with a Reduction in Prefrontal Cortical miR-1971 Expression Levels in a Mouse Model of Posttraumatic Stress Disorder

“…To analyze the impact of traumatic stress on miRNA profiles in mouse PFC, we employed a well-established mouse model for PTSD that we (28, 29, 41–43) and also other research groups used, at least in slightly modified ways (44–46), for previous experiments. The electric footshock-elicited murine PTSD-like syndrome can be effectively counteracted by the orally administered SSRI antidepressant fluoxetine (28, 29) and, as we published recently, lasts at least until day 60 after shock application (28).…”

“…Experiments were performed during the activity phase of the mice, i.e., between 9:30 a.m. and 6:00 p.m., employing our established PTSD mouse model which we described in detail previously (28, 29). Briefly, 10-week-old male C57BL/6NCrl mice were subjected to a single 1.5 mA electric footshock for 2 s or mock treatment (exposure to shock chamber, the latter is termed “shock context” or “shock chamber” in the following).…”

“…Here, we present the first study exploring the connection between miRNAs and the PTSD-like syndrome in rodents. Using a miRNA microarray, we analyzed miRNA profiles in our previously established mouse model for PTSD (28, 42). In detail, we compared miRBase 18.0 based miRNA profiles in PFC samples of four groups of mice, i.e., footshocked and non-footshocked mice which were either fluoxetine-treated or untreated.…”

Animal models of anxiety disorders and stress

“…Like other stress protocols, electric foot shocks can be combined with anxiety tests. 125,126 Social defeat stress…”

Fluoxetine Treatment Rescues Energy Metabolism Pathway Alterations in a Posttraumatic Stress Disorder Mouse Model

“…We applied an FS-induced PTSD model using inbred C57BL/6NCrl mice, a strain that is susceptible to PTSD-like symptom development [16,18,27,28,29]. Using a standardized proteomics platform based on 15 N metabolic labeling and mass spectrometry, we accurately quantified and identified significantly altered protein expression levels in affected brain regions and enriched altered cellular pathways by in silico pathway analyses.…”