Mahar I, Labonte B, Yogendran S, Isingrini E, Perret L, Davoli M A, Rachalski A, Giros B, Turecki G, Mechawar N
McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada.
Transl Psychiatry. 2017 Jul 4;7(7):e1161. doi: 10.1038/tp.2017.132.
Neuregulin-1 (NRG1) and ErbB receptors have been associated with psychopathology, and NRG1-ErbB3 signaling has been shown to increase hippocampal neurogenesis and induce antidepressant-like effects. In this study, we aimed to determine whether deficits in NRG1 or ErbBs might be present in the hippocampus of suicide completers. In well-characterized postmortem hippocampal samples from suicides and matched sudden-death controls, we assessed gene expression and methylation using qRT-PCR and EpiTYPER, respectively. Moreover, in hippocampal tissues stained with cresyl violet, stereology was used to quantify numbers of granule cells and of glia. Granule cell body size was examined with a nucleator probe, and granule cell layer volume with a Cavalieri probe. Unmedicated suicides showed sharply decreased hippocampal ErbB3 expression and decreased numbers of ErbB3-expressing granule cell neurons in the anterior dentate gyrus; a phenomenon seemingly reversed by antidepressant treatment. Furthermore, we found ErbB3 expression to be significantly decreased in the dentate gyrus of adult mice exposed to chronic social defeat stress. Taken together, these results reveal novel suicidal endophenotypes in the hippocampus, as well as a putative etiological mechanism underlying suicidality, and suggest that antidepressant or NRG1 treatment may reverse a potential deficit in anterior dentate gyrus granule cell neurons in individuals at risk of dying by suicide.
神经调节蛋白-1（NRG1）和表皮生长因子受体（ErbB）与精神病理学有关，并且已表明NRG1-ErbB3信号传导可增加海马神经发生并诱导抗抑郁样效应。在本研究中，我们旨在确定自杀身亡者的海马体中是否存在NRG1或ErbB的缺陷。在来自自杀者和匹配的猝死对照的特征明确的死后海马样本中，我们分别使用qRT-PCR和EpiTYPER评估基因表达和甲基化。此外，在经甲酚紫染色的海马组织中，使用体视学方法对颗粒细胞和神经胶质细胞的数量进行量化。用成核探针检查颗粒细胞体大小，用卡瓦列里探针检查颗粒细胞层体积。未接受药物治疗的自杀者海马体中ErbB3表达急剧下降，前齿状回中表达ErbB3的颗粒细胞神经元数量减少；这一现象似乎可通过抗抑郁治疗得到逆转。此外，我们发现成年小鼠在遭受慢性社会挫败应激后，齿状回中ErbB3表达显著下降。综上所述，这些结果揭示了海马体中新型的自杀内表型，以及自杀行为潜在的病因机制，并表明抗抑郁药或NRG1治疗可能会逆转有自杀死亡风险个体前齿状回颗粒细胞神经元的潜在缺陷。
