Penninck Lukas, Ibrahim El Chérif, Artiges Eric, Gorgievski Victor, Desrivières Sylvane, Farley Severine, Filippi Irina, de Macedo Carlos E A, Belzeaux Raoul, Banaschewski Tobias, Bokde Arun L W, Quinlan Erin Burke, Flor Herta, Grigis Antoine, Garavan Hugh, Gowland Penny, Heinz Andreas, Brühl Rüdiger, Nees Frauke, Papadopoulos Orfanos Dimitri, Paus Tomáš, Poustka Luise, Fröhner Juliane H, Smolka Michael N, Walter Henrik, Whelan Robert, Grenier Julien, Schumann Gunter, Paillère Martinot Marie-Laure, Tzavara Eleni T, Martinot Jean-Luc
Institut National de la Santé et de la Recherche Médicale, INSERM U1299 "Trajectoires Développementales en Psychiatrie", Université Paris-Saclay, Ecole Normale Supérieure Paris-Saclay, CNRS, Centre Borelli, Gif-sur-Yvette, France.
Aix Marseille Univ, CNRS, INT, Inst Neurosci Timone, Marseille, France.
Front Syst Neurosci. 2021 Sep 30;15:725413. doi: 10.3389/fnsys.2021.725413. eCollection 2021.
Adolescence is a period of vulnerability for the maturation of gray matter (GM) and also for the onset of psychiatric disorders such as major depressive disorder (MDD), bipolar disorder and schizophrenia. Chronic neuroinflammation is considered to play a role in the etiology of these illnesses. However, the involvement of neuroinflammation in the observed link between regional GM volume reductions and psychiatric symptoms is not established yet. Here, we investigated a possible common immune-related genetic link between these two phenomena in european adolescents recruited from the community. Hippocampal and medial prefrontal cortex (mPFC) were defined as regions of interest (ROIs). Their GM volumes were extracted in 1,563 14-year-olds from the IMAGEN database. We found a set of 26 SNPs that correlated with the hippocampal volumes and 29 with the mPFC volumes at age 14. We formed two ROI-Related Immune-gene scores (RRI) with the inflammation SNPs that correlated to hippocampal GM volume and to mPFC GM volume. The predictive ability of both RRIs with regards to the presence of psychiatric symptoms at age 18 was investigated by correlating the RRIs with psychometric questionnaires obtained at age 18. The RRIs (but not control scores constructed with random SNPs) correlated with the presence of depressive symptoms, positive psychotic symptoms, and externalizing symptoms in later adolescence. In addition, the effect of childhood maltreatment, one of the major environmental risk factors for depression and other mental disorders, interacted with the RRI effect. We next sought to validate this finding by investigating our set of inflammatory genes in a translational animal model of early life adversity. Mice were subjected to a protocol of maternal separation at an early post-natal age. We evaluated depressive behaviors in separated and non-separated mice at adolescence and their correlations with the concomitant expression of our genes in whole blood samples. We show that in mice, early life adversity affected the expression of our set of genes in peripheral blood, and that levels of expression correlated with symptoms of negative affect in adolescence. Overall, our translational findings in adolescent mice and humans provide a novel validated gene-set of immune-related genes for further research in the early stages of mood disorders.
青春期是灰质（GM）成熟的脆弱时期，也是诸如重度抑郁症（MDD）、双相情感障碍和精神分裂症等精神疾病发病的脆弱时期。慢性神经炎症被认为在这些疾病的病因中起作用。然而，神经炎症在观察到的区域GM体积减少与精神症状之间的联系中的作用尚未确定。在这里，我们在从社区招募的欧洲青少年中研究了这两种现象之间可能存在的共同免疫相关基因联系。海马体和内侧前额叶皮质（mPFC）被定义为感兴趣区域（ROIs）。从IMAGEN数据库中提取了1563名14岁青少年的GM体积数据。我们发现一组26个单核苷酸多态性（SNPs）与14岁时的海马体体积相关，29个与mPFC体积相关。我们用与海马体GM体积和mPFC GM体积相关的炎症SNPs形成了两个ROI相关免疫基因分数（RRI）。通过将RRI与18岁时获得的心理测量问卷进行关联，研究了这两个RRI对18岁时精神症状存在情况的预测能力。RRI（但不是用随机SNPs构建的对照分数）与青少年后期抑郁症状、阳性精神病性症状和外化症状的存在相关。此外，童年期虐待这一抑郁症和其他精神障碍的主要环境风险因素之一，与RRI效应相互作用。接下来，我们试图通过在早期生活逆境的转化动物模型中研究我们的一组炎症基因来验证这一发现。在出生后早期对小鼠进行母体分离方案。我们评估了青春期分离和未分离小鼠的抑郁行为，以及它们与全血样本中我们基因的伴随表达之间的相关性。我们表明，在小鼠中，早期生活逆境影响了我们这组基因在外周血中的表达，并且表达水平与青春期的消极情绪症状相关。总体而言，我们在青少年小鼠和人类中的转化研究结果提供了一组经过验证的新型免疫相关基因，用于情绪障碍早期阶段的进一步研究。
