Searching for glycomic biomarkers for predicting resilience and vulnerability in a rat model of posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is triggered by traumatic events in 10–20% of exposed subjects. N-linked glycosylation, by modifying protein functions, may provide an important environmental link predicting vulnerability. Our goals were (1) to find alterations in plasma N-glycome predicting stress-vulnerability; (2) to investigate how trauma affects N-glycome in the plasma (PGP) and in three PTSD-related brain regions (prefrontal cortex, hippocampus and amygdala; BGP), hence, uncover specific targets for PTSD treatment. We examined male (1) controls, (2) traumatized vulnerable and (3) traumatized resilient rats both before and several weeks after electric footshock. Vulnerable and resilient groups were separated by z-score analysis of behavior. Higher freezing behavior and decreased social interest were detected in vulnerable groups compared to control and resilient rats. Innate anxiety did not predict vulnerability, but pretrauma levels of PGP10(FA1G1Ga1), PGP11(FA2G2), and PGP15(FA3G2) correlated positively with it, the last one being the most sensitive. Traumatic stress induced a shift from large, elaborate N-glycans toward simpler neutral structures in the plasma of all traumatized animals and specifically in the prefrontal cortex of vulnerable rats. In plasma trauma increased PGP17(A2G2S) level in vulnerable animals. In all three brain regions, BGP11(F(6)A2B) was more abundant in vulnerable rats, while most behavioral correlations occurred in the prefrontal cortex. In conclusion, we found N-glycans (especially PGP15(FA3G2)) in plasma as possible biomarkers of vulnerability to trauma that warrants further investigation. Posttrauma PGP17(A2G2S1) increase showed overlap with human results highlighting the utility and relevance of this animal model. Prefrontal cortex is a key site of trauma-induced glycosylation changes that could modulate the behavioral outcome.

创伤后应激障碍（Posttraumatic stress disorder, PTSD）在10%~20%的创伤暴露个体中会被触发。N-连接糖基化（N-linked glycosylation）可通过调控蛋白质功能，成为预测创伤易感性的重要环境关联因素。本研究的目标包括：（1）筛选可预测应激易感性的血浆N-糖组（plasma N-glycome）异常变化；（2）探究创伤如何影响血浆糖组（plasma glycome, PGP）以及前额叶皮层（prefrontal cortex）、海马体（hippocampus）、杏仁核（amygdala）这三个与PTSD相关的脑区的脑糖组（brain glycome, BGP），进而明确PTSD治疗的特异性潜在靶点。我们对雄性大鼠开展了实验，分别在电足电击（electric footshock）前及电击数周后，对三组大鼠进行检测：（1）对照组、（2）创伤易感组与（3）创伤抵抗组；其中易感组与抵抗组通过行为学的z分数分析（z-score analysis）进行划分。相较于对照组与抵抗组大鼠，易感组大鼠表现出更高的僵住行为（freezing behavior）与更低的社交兴趣。先天焦虑水平无法预测创伤易感性，但创伤前血浆中PGP10(FA1G1Ga1)、PGP11(FA2G2)与PGP15(FA3G2)的水平与易感性呈正相关，其中PGP15(FA3G2)的相关性最为显著。创伤应激可使所有创伤暴露大鼠的血浆N-糖组发生重塑：从结构复杂的大型N-聚糖转向更为简单的中性聚糖结构，该变化在易感大鼠的前额叶皮层中尤为突出。在易感大鼠的血浆中，创伤后PGP17(A2G2S)的水平显著升高。在三个目标脑区中，易感大鼠的BGP11(F(6)A2B)丰度均更高，且多数行为学相关性均出现在前额叶皮层。综上，本研究发现血浆中的N-聚糖（尤其是PGP15(FA3G2)）可作为创伤易感性的潜在生物标志物，值得开展进一步研究。创伤后血浆PGP17(A2G2S1)的水平升高与人类相关研究结果存在重合，凸显了该动物模型的实用性与研究价值。前额叶皮层是创伤诱导的糖基化变化的关键位点，该变化可调控行为学结局。