Musazzi Laura, Mallei Alessandra, Tardito Daniela, Gruber Susanne H M, El Khoury Aram, Racagni Giorgio, Mathé Aleksander A, Popoli Maurizio
Center of Neuropharmacology, Department of Pharmacological Sciences, Center of Excellence on Neurodegenerative Diseases, University of Milano, Italy.
J Psychiatr Res. 2010 Jun;44(8):511-20. doi: 10.1016/j.jpsychires.2009.11.008. Epub 2009 Dec 8.
Stress has been shown to interact with genetic vulnerability in pathogenesis of psychiatric disorders. Here we investigated the outcome of interaction between genetic vulnerability and early-life stress, by employing a rodent model that combines an inherited trait of vulnerability in Flinders Sensitive Line (FSL) rats, with early-life stress (maternal separation). Basal differences in synaptic signaling between FSL rats and their controls were studied, as well as the consequences of early-life stress in adulthood, and their response to chronic antidepressant treatment (escitalopram). FSL rats showed basal differences in the activation of synapsin I and Erk1/2, as well as in alpha CaM kinase II/syntaxin-1 and alpha CaM kinase II/NMDA-receptor interactions in purified hippocampal synaptosomes. In addition, FSL rats displayed a blunted response of Erk-MAP kinases and other differences in the outcome of early-life stress in adulthood. Escitalopram treatment restored some but not all alterations observed in FSL rats after early-life stress. The marked alterations found in key regulators of presynaptic release/neurotransmission in the basal FSL rats, and as a result of early-life stress, suggest synaptic dysfunction. These results show that early gene-environment interaction may cause life-long synaptic changes affecting the course of depressive-like behavior and response to drugs.
应激已被证明在精神疾病的发病机制中与遗传易感性相互作用。在此，我们通过采用一种啮齿动物模型来研究遗传易感性与早年应激之间相互作用的结果，该模型将弗林德斯敏感品系（FSL）大鼠的遗传易感性特征与早年应激（母婴分离）相结合。我们研究了FSL大鼠与其对照之间突触信号传导的基础差异，以及成年期早年应激的后果，及其对慢性抗抑郁治疗（艾司西酞普兰）的反应。FSL大鼠在突触素I和Erk1/2的激活方面，以及在纯化的海马突触体中α钙调蛋白激酶II/ syntaxin - 1和α钙调蛋白激酶II/NMDA受体相互作用方面表现出基础差异。此外，FSL大鼠在成年期对早年应激的反应中，Erk - MAP激酶反应迟钝，且存在其他差异。艾司西酞普兰治疗恢复了早年应激后FSL大鼠中观察到的部分但并非全部改变。在基础状态的FSL大鼠中以及早年应激导致的突触前释放/神经传递关键调节因子的显著改变提示突触功能障碍。这些结果表明，早期基因 - 环境相互作用可能导致终生的突触变化，影响抑郁样行为的进程和对药物的反应。
