Sitbon Jérémy, Nestvogel Dennis, Kappeler Caroline, Nicolas Aude, Maciuba Stephanie, Henrion Annabelle, Troudet Réjane, Courtois Elisa, Grannec Gaël, Latapie Violaine, Barau Caroline, Le Corvoisier Philippe, Pietrancosta Nicolas, Henry Chantal, Leboyer Marion, Etain Bruno, Nosten-Bertrand Marika, Martin Thomas F J, Rhee JeongSeop, Jamain Stéphane
Univ Paris Est Créteil, INSERM, IMRB, Translational Neuropsychiatry, Créteil, France.
Fondation FondaMental, Créteil, France.
Mol Psychiatry. 2022 Feb;27(2):1145-1157. doi: 10.1038/s41380-021-01151-9. Epub 2022 Feb 15.
Bipolar disorder is a severe and chronic psychiatric disease resulting from a combination of genetic and environmental risk factors. Here, we identified a significant higher mutation rate in a gene encoding the calcium-dependent activator protein for secretion (CADPS) in 132 individuals with bipolar disorder, when compared to 184 unaffected controls or to 21,070 non-psychiatric and non-Finnish European subjects from the Exome Aggregation Consortium. We found that most of these variants resulted either in a lower abundance or a partial impairment in one of the basic functions of CADPS in regulating neuronal exocytosis, synaptic plasticity and vesicular transporter-dependent uptake of catecholamines. Heterozygous mutant mice for Cadps revealed that a decreased level of CADPS leads to manic-like behaviours, changes in BDNF level and a hypersensitivity to stress. This was consistent with more childhood trauma reported in families with mutation in CADPS, and more specifically in mutated individuals. Furthermore, hyperactivity observed in mutant animals was rescued by the mood-stabilizing drug lithium. Overall, our results suggest that dysfunction in calcium-dependent vesicular exocytosis may increase the sensitivity to environmental stressors enhancing the risk of developing bipolar disorder.
双相情感障碍是一种由遗传和环境风险因素共同作用导致的严重慢性精神疾病。在此，我们发现，与184名未受影响的对照者或外显子聚合联盟中21,070名非精神科且非芬兰裔欧洲受试者相比，132名双相情感障碍患者中，一种编码分泌型钙依赖性激活蛋白（CADPS）的基因的突变率显著更高。我们发现，这些变异中的大多数要么导致CADPS在调节神经元胞吐、突触可塑性和囊泡转运体依赖性儿茶酚胺摄取等基本功能之一中的丰度降低，要么导致其部分受损。Cadps杂合突变小鼠显示，CADPS水平降低会导致躁狂样行为、脑源性神经营养因子（BDNF）水平变化以及对应激的超敏反应。这与CADPS发生突变的家庭中报告的更多童年创伤情况一致，尤其是在突变个体中。此外，突变动物中观察到的多动现象可通过心境稳定剂锂得到缓解。总体而言，我们的结果表明，钙依赖性囊泡胞吐功能障碍可能会增加对环境应激源的敏感性，从而增加患双相情感障碍的风险。
