Methyl-CpG binding protein 2 functional alterations provide vulnerability to develop behavioral and molecular features of post-traumatic stress disorder in male mice

• Published in: Neuropharmacology Vol. 160; p. 107664
• Main Authors: Cosentino, Livia, Vigli, Daniele, Medici, Vanessa, Flor, Herta, Lucarelli, Marco, Fuso, Andrea, De Filippis, Bianca
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2019
• Subjects: Avoidance; Epigenetics; MeCP2; Memory; PTSD; Susceptibility; PTSD; Epigenetics; MeCP2; Susceptibility; Memory; Avoidance
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2019.06.003

Post-traumatic stress disorder (PTSD) is a mental disorder characterized by symptoms of persistent anxiety arising after exposure to traumatic events. Stress susceptibility due to a complex interplay between genetic and environmental factors plays a major role in the disease etiology, although biological underpinnings have not been clarified. We hypothesized that aberrant functionality of the methyl-CpG binding protein 2 (MECP2), a master regulator of experience-dependent epigenetic programming, confers susceptibility to develop PTSD-like symptomatology in the aftermath of traumatic events. Transgenic male mice expressing a truncated form of MeCP2 protein (MeCP2-308) were exposed at adulthood to a trauma in the form of high-intensity footshocks. The presence and duration of PTSD-like symptoms were assessed and compared to those of trauma-exposed wild type littermates and MeCP2-308 mice subjected to a mild stressor. The effects of fluoxetine, a prime pharmacological PTSD treatment, on PTSD-like symptomatology were also explored. Trauma-exposed MeCP2-308 mice showed long-lasting hyperresponsiveness to both correct and incorrect predictors of the trauma and persistent increased avoidance of trauma-related cues. Traumatized MeCP2-308 mice also displayed abnormal post-traumatic plasma levels of the stress hormone corticosterone and altered peripheral gene expression mirroring that of PTSD patients. Fluoxetine improved PTSD-like symptoms in trauma-exposed MeCP2-308 mice. These findings provide evidence that MeCP2 dysfunction results in increased susceptibility to develop PTSD-like symptoms after trauma exposure, and identify trauma-exposed MeCP2-308 mice as a new tool to investigate the underpinnings of PTSD vulnerability. •MeCP2-308 mice traumatized at adulthood display long-lasting memory alterations.•Trauma-exposed MeCP2-308 mice develop persistent avoidance behavior.•Fluoxetine partially reverses behavioral aberrancies of traumatized MeCP2-308 mice.•MeCP2-308 mice showed aberrant increase of corticosterone acutely after trauma.•Traumatized mutant mice mirrored patients' peripheral gene expression alterations.