Mallei Alessandra, Failler Marion, Corna Stefano, Racagni Giorgio, Mathé Aleksander A, Popoli Maurizio
Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmacologiche e Biomolecolari and Center of Excellence on Neurodegenerative Diseases, University of Milano, Milano, Italy (Drs Mallei, Failler, Corna, Racagni, and Popoli); Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden (Dr Mathé).
Int J Neuropsychopharmacol. 2014 Oct 31;18(3):pyu067. doi: 10.1093/ijnp/pyu067.
Major depression is a severe mental illness that causes heavy social and economic burdens worldwide. A number of studies have shown that interaction between individual genetic vulnerability and environmental risk factors, such as stress, is crucial in psychiatric pathophysiology. In particular, the experience of stressful events in childhood, such as neglect, abuse, or parental loss, was found to increase the risk for development of depression in adult life. Here, to reproduce the gene x environment interaction, we employed an animal model that combines genetic vulnerability with early-life stress.
The Flinders Sensitive Line rats (FSL), a validated genetic animal model of depression, and the Flinders Resistant Line (FRL) rats, their controls, were subjected to a standard protocol of maternal separation (MS) from postnatal days 2 to 14. A basal comparison between the two lines for the outcome of the environmental manipulation was performed at postnatal day 73, when the rats were into adulthood. We carried out a global proteomic analysis of purified synaptic terminals (synaptosomes), in order to study a subcellular compartment enriched in proteins involved in synaptic function. Two-dimensional gel electrophoresis (2-DE), mass spectrometry, and bioinformatic analysis were used to analyze proteins and related functional networks that were modulated by genetic susceptibility (FSL vs. FRL) or by exposure to early-life stress (FRL + MS vs. FRL and FSL + MS vs.
FSL) RESULTS: We found that, at a synaptic level, mainly proteins and molecular pathways related to energy metabolism and cellular remodeling were dysregulated.
The present results, in line with previous works, suggest that dysfunction of energy metabolism and cytoskeleton dynamics at a synaptic level could be features of stress-related pathologies, in particular major depression.
重度抑郁症是一种严重的精神疾病，在全球范围内造成沉重的社会和经济负担。多项研究表明，个体遗传易感性与环境风险因素（如压力）之间的相互作用在精神病理生理学中至关重要。特别是，童年时期经历的应激事件，如忽视、虐待或父母离世，被发现会增加成年后患抑郁症的风险。在此，为了重现基因与环境的相互作用，我们采用了一种将遗传易感性与早期生活压力相结合的动物模型。
弗林德斯敏感系大鼠（FSL）是一种经过验证的抑郁症遗传动物模型，其对照为弗林德斯抗性系（FRL）大鼠，在出生后第2天至第14天接受标准的母婴分离（MS）方案。在出生后第73天，当大鼠成年时，对两系动物进行环境操纵结果的基础比较。我们对纯化的突触终末（突触体）进行了全蛋白质组分析，以研究富含参与突触功能蛋白质的亚细胞区室。采用二维凝胶电泳（2-DE）、质谱分析和生物信息学分析来分析受遗传易感性（FSL与FRL）或早期生活压力暴露（FRL + MS与FRL以及FSL + MS与FSL）调节的蛋白质及相关功能网络。
我们发现，在突触水平上，主要是与能量代谢和细胞重塑相关的蛋白质和分子途径失调。
本研究结果与先前的研究一致，表明突触水平上能量代谢和细胞骨架动力学功能障碍可能是应激相关疾病（尤其是重度抑郁症）的特征。
