Abstract
Background: Genetic factors pertinent to Parkinson's disease (PD) might predispose an individual to post-traumatic stress disorder (PTSD). Humans who are heterozygous for the glucocerebrosidase 1 (GBA) L444P Gaucher mutation have an increased PD risk and elevated levels of alpha synuclein (aSyn). Mice that are heterozygous for the GBA mutation and express aSyn with the A53T mutation show elevated anxiety levels at 20 months of age compared to those expressing only A53T. Objective: This study aims to assess whether A53T and A53T-L444P affect the risk of developing PTSD phenotypes and whether sex and age modulate this risk. Methods: Young (5.1 ± 0.2 months) and older (11.3 ± 0.2 months) A53T and GBA L444P female and male mice were tested for fear learning and memory extinction in the contextual fear conditioning and passive avoidance paradigms. Subsequently, the mice were tested for measures of activity and anxiety in the open field and for depressive-like behavior in the forced swim test. Results: In the contextual fear memory extinction paradigm, only young A53T female mice showed contextual fear memory extinction, while older A53T female mice showed increased activity levels over subsequent days. In the passive avoidance memory paradigm, no mice showed extinction of passive avoidance memory. When the frequency of entering the more anxiety-provoking center of the open field was analyzed, a test history x sex x age interaction was observed. In the forced swim test, test history affected the depressive-like behavior in mice trained; there was more depressive-like behavior in mice trained in the contextual fear memory extinction paradigm than in mice trained in the passive avoidance memory extinction paradigm. Moreover, there was an effect of age with more depressive-like behavior in older than in younger mice, and an effect of genotype with more depressive-like behavior in A53T-L444P compared to A53T mice. When cortical phosphorylated tau (pS 199) levels were analyzed, there was an effects of genotype, a sex x age interaction, and ant age x test history interaction. Conclusions: A53T and A53T-L444P affect the risk of developing PTSD phenotypes. Fear extinction test history, genotype, and age affect depressive-like behavior and tau pathology.