Bunnell Emily, Saltonstall Elizabeth, Pederson Alexandra, Baxter Charlie, Ramicciotti Elia, Robinson Naomi, Sandholm Phoebe, O Niel Abigail, Raber Jacob
Department of Behavioral Neuroscience, L470, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Departments of Neurology, Psychiatry, and Radiation Medicine, Division of Neuroscience ONPRC, Oregon Health & Science University, Portland, OR 97239, USA.
Genes (Basel). 2025 Aug 26;16(9):1004. doi: 10.3390/genes16091004.
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. 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. 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. 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. 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.
与帕金森病（PD）相关的遗传因素可能使个体易患创伤后应激障碍（PTSD）。携带葡萄糖脑苷脂酶1（GBA）L444P戈谢突变的杂合子人类患PD的风险增加，且α-突触核蛋白（aSyn）水平升高。携带GBA突变的杂合子小鼠以及表达A53T突变型aSyn的小鼠在20月龄时的焦虑水平高于仅表达A53T突变型aSyn的小鼠。本研究旨在评估A53T和A53T-L444P是否会影响PTSD表型的发生风险，以及性别和年龄是否会调节这种风险。对年轻（5.1±0.2个月）和年长（11.3±0.2个月）的A53T和GBA L444P雌性和雄性小鼠进行情境恐惧条件反射和被动回避范式中的恐惧学习和记忆消退测试。随后，对小鼠进行旷场实验中的活动和焦虑测量以及强迫游泳实验中的抑郁样行为测量。在情境恐惧记忆消退范式中，只有年轻的A53T雌性小鼠表现出情境恐惧记忆消退，而年长的A53T雌性小鼠在随后几天的活动水平增加。在被动回避记忆范式中，没有小鼠表现出被动回避记忆的消退。当分析进入旷场中更易引发焦虑的中心区域的频率时，观察到测试历史×性别×年龄的交互作用。在强迫游泳实验中，测试历史影响训练小鼠的抑郁样行为；在情境恐惧记忆消退范式中训练的小鼠比在被动回避记忆消退范式中训练的小鼠有更多的抑郁样行为。此外，存在年龄效应，年长小鼠比年轻小鼠有更多的抑郁样行为，以及基因型效应，与A53T小鼠相比，A53T-L444P小鼠有更多的抑郁样行为。当分析皮质磷酸化tau（pS 199）水平时，存在基因型效应、性别×年龄交互作用以及年龄×测试历史交互作用。A53T和A53T-L444P影响PTSD表型的发生风险。恐惧消退测试历史、基因型和年龄影响抑郁样行为和tau病理。
