Dwivedi Yogesh, Zhang Hui
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Neural Plast. 2016;2016:7383724. doi: 10.1155/2016/7383724. Epub 2015 Dec 29.
Extracellular signal-regulated kinase 1/2- (ERK1/2-) mediated cellular signaling plays a major role in synaptic and structural plasticity. Although ERK1/2 signaling has been shown to be involved in stress and depression, whether vulnerability to develop depression is associated with abnormalities in ERK1/2 signaling is not clearly known. The present study examined ERK1/2 signaling in frontal cortex and hippocampus of rats that showed vulnerability (learned helplessness, (LH)) or resiliency (non-learned helplessness, (non-LH)) to developing stress-induced depression. In frontal cortex and hippocampus of LH rats, we found that mRNA and protein expressions of ERK1 and ERK2 were significantly reduced, which was associated with their reduced activation and phosphorylation in cytosolic and nuclear fractions, where ERK1 and ERK2 target their substrates. In addition, ERK1/2-mediated catalytic activities and phosphorylation of downstream substrates RSK1 (cytosolic and nuclear) and MSK1 (nuclear) were also lower in the frontal cortex and hippocampus of LH rats without any change in their mRNA or protein expression. None of these changes were evident in non-LH rats. Our study indicates that ERK1/2 signaling is differentially regulated in LH and non-LH rats and suggests that abnormalities in ERK1/2 signaling may be crucial in the vulnerability to developing depression.
细胞外信号调节激酶1/2（ERK1/2）介导的细胞信号传导在突触和结构可塑性中起主要作用。尽管已表明ERK1/2信号传导与应激和抑郁有关，但尚不清楚患抑郁症的易感性是否与ERK1/2信号传导异常有关。本研究检测了对压力诱导的抑郁表现出易感性（习得性无助，LH）或恢复力（非习得性无助，非LH）的大鼠额叶皮质和海马中的ERK1/2信号传导。在LH大鼠的额叶皮质和海马中，我们发现ERK1和ERK2的mRNA和蛋白表达显著降低，这与其在胞质和核组分中的激活和磷酸化降低有关，ERK1和ERK2在这些组分中作用于其底物。此外，LH大鼠额叶皮质和海马中ERK1/2介导的下游底物RSK1（胞质和核）和MSK1（核）的催化活性和磷酸化也较低，而它们的mRNA或蛋白表达没有任何变化。这些变化在非LH大鼠中均不明显。我们的研究表明，ERK1/2信号传导在LH和非LH大鼠中受到不同调节，并提示ERK1/2信号传导异常可能在患抑郁症的易感性中起关键作用。
