[Neurological mechanism and therapeutic strategy for posttraumatic stress disorders]

Posttraumatic stress disorder (PTSD) is most often induced by traumatic events and serious public health problems. PTSD is characterized by excessive response to contextual memory and impaired fear extinction and also associated with mild cognitive impairment, attention and learning deficits. Clinical and animal studies suggest that increased susceptibility of emotion- and fear-related neuronal circuits, including those in the amygdala, prefrontal cortex and hippocampus, contributes to development and retention of PTSD symptoms. However, mechanisms underlying this susceptibility to fear are not known and the useful therapeutic approaches are limited. Recently, there have been reports that ω3 LCPUFA supplementation can prevent development of PTSD and significantly ameliorate symptoms in patients with PTSD after accidental injury such as motor vehicle accidents and natural calamities. Importantly, Fabp7 null mice exhibit enhancement of fear memory consolidation and anxiety-related behaviors that resemble PTSD-like behaviors in humans. In this review, we focused behavioral phenotype of PTSD in Fabp3 null mice. The Fabp3 null mice exhibit cognitive deficits, hyperlocomotion and impaired fear extinction, and thus show PTSD-like behaviors. Chronic administration of ramelteon, a melatonin receptor agonist, improved all PTSD-like behaviors tested in Fabp3^－/－ mice. Relevant to mechanisms underlying impaired fear extinction, we observed that Ca^2＋/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation increases in the basolateral amygdala (BLA) but remained unchanges in the hippocampus of Fabp3^－/－ mice. Likewise, the number of c-Fos positive neurons in BLA significantly increased after exposure to contextual fear conditions. Finally, chronic ramelteon administration restored abnormal c-Fos expression and CaMKII autophosphorylation in the BLA of Fabp3^－/－ mice. Taken together, Fabp3^－/－ mice show PTSD-like behaviors, and ramelteon is an attractive candidate for PTSD therapeutics in human.