Clinical Therapeutic Strategy and Neuronal Mechanism Underlying Post-Traumatic Stress Disorder (PTSD)

Abstract

Post-traumatic stress disorder (PTSD) is characterized by an exaggerated response to contextual memory and impaired fear extinction, with or without mild cognitive impairment, learning deficits, and nightmares. PTSD is often developed by traumatic events, such as war, terrorist attack, natural calamities, etc. Clinical and animal studies suggest that aberrant susceptibility of emotion- and fear-related neurocircuits, including the amygdala, prefrontal cortex (PFC), and hippocampus may contribute to the development and retention of PTSD symptoms. Psychological and pharmacological therapy, such as cognitive behavioral therapy (CBT), and treatment with anti-depressive agents and/or antipsychotics significantly attenuate PTSD symptoms. However, more effective therapeutics are required for improvement of quality of life in PTSD patients. Previous studies have reported that ω3 long-chain polyunsaturated fatty acid (LCPUFA) supplements can suppress the development of PTSD symptoms. Fatty acid binding proteins (FABPs) are essential for LCPUFA intracellular trafficking. In this review, we have introduced Fabp3 null mice as an animal model of PTSD with impaired fear extinction. Moreover, we have addressed the neuronal circuits and novel therapeutic strategies for PTSD symptoms.

Keywords: calcium/calmodulin-dependent protein kinase II; fatty acid binding protein 3; post-traumatic stress disorder; ramelteon.

Figure 1

Experimental apparatus and design for evaluation of fear extinction. (A) Schematic diagram of contextual fear memory in passive avoidance task to evaluate fear extinction in the mouse. (B) Experimental schedule for assessment of fear extinction. Mice received an electric shock (0.5 mA for 3 s) once a day for four consecutive days (fear acquisition). After that, the mouse was exposed to the light box, and step-through latency was measured without an electric shock (fear extinction). D: Day.

Figure 2

Impaired fear extinction processing in Fabp3 null mice. (A) Overview of fear responses as elapsed time during the acquisition (Day 1 to 4) and extinction phase (Day 5 to 35) (n = 4–11 per group). (B) Ramelteon (1.0 mg/kg, p.o.) repaired the impaired fear extinction process in Fabp3 null mice from Day 15 to 35, an effect prevented by luzindole (2.5 mg/kg, i.p.) treatment (n = 4–11 per group). Error bars represent SEM. * p < 0.05 vs. vehicle-treated wild-type (WT) mice; ** p < 0.01 vs. vehicle-treated WT mice; # p < 0.05 vs. vehicle-treated Fabp3 null mice; ## p < 0.01 vs. vehicle-treated Fabp3 null mice; † p < 0.05 vs. ramelteon (1.0 mg/kg, p.o.)-treated Fabp3 null mice. Luz, luzindole (2.5 mg/kg, i.p.) treatment; Ram 1.0, ramelteon (1.0 mg/kg, p.o.) treatment; veh, vehicle treatment. Modified data derived from Reference [156].

Figure 3

Aberrant c-Fos expression and CaMKII autophosphorylation levels in the basolateral amygdala (BLA) in Fabp3 null mice. (A) Representative images of BLA in each group of mice one hour after the extinction test on Day 35. The effect of ramelteon (1.0 mg/kg, p.o.) on the elevated level of c-Fos was antagonized by luzindole (2.5 mg/kg, i.p.) treatment in Fabp3 null mice. Scale bars: 100 µm. (B) Representative images of BLA in WT and Fabp3 null mice stained by phosphorylated CaMKII (red) and c-Fos (green). Increased c-Fos expression levels were observed in elevated autophosphorylation CaMKII-positive cells in BLA of Fabp3 null mice. Modified data derived from Reference [156].

Figure 4

The hypothesis of neuronal circuits in the fear extinction in WT and Fabp3 null mice. (Left) Contextual fear memory is acquired in the hippocampus and then consolidated and retrieved in the BLA. The ACC negatively regulates neuronal activity in BLA, resulting in suppression of exacerbated fear retrieval and facilitation of fear extinction in WT mice. (Right) Hypofunction in the ACC fails to inhibit aberrant neuronal activity in the BLA, leading to the development of aberrant fear retrieval and impaired fear extinction in Fabp3 null mice. Ramelteon improves decreased neuronal activity in the ACC through stimulation of the melatonin receptors. Therefore, ramelteon improves the impaired fear extinction by suppressing hyperactivation of BLA in Fabp3 null mice (Right). Modified data derived from Reference [170].