Departments of Pharmacology and Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
J Neurosci. 2013 Aug 21;33(34):13673-85. doi: 10.1523/JNEUROSCI.1669-13.2013.
The transcription factor cAMP response element-binding protein (CREB) has been implicated in the pathophysiology of depression as well as in the efficacy of antidepressant treatment. However, altering CREB levels appears to have differing effects on anxiety- and depression-related behaviors, depending on which brain region is examined. Furthermore, many manipulations of CREB lead to corresponding changes in other CREB family proteins, and the impact of these changes has been largely ignored. To further investigate the region-specific importance of CREB in depression-related behavior and antidepressant response, we used Creb(loxP/loxP) mice to localize CREB deletion to the hippocampus. In an assay sensitive to chronic antidepressant response, the novelty-induced hypophagia procedure, hippocampal CREB deletion, did not alter the response to chronic antidepressant treatment. In contrast, mice with hippocampal CREB deletion responded to acute antidepressant treatment in this task, and this accelerated response was accompanied by an increase in hippocampal neurogenesis. Upregulation of the CREB-family protein cAMP response-element modulator (CREM) was observed after CREB deletion. Viral overexpression of the activator isoform of CREM, CREMτ, in the hippocampus also resulted in an accelerated response to antidepressants as well as increased hippocampal neurogenesis. This is the first demonstration of CREMτ within the brain playing a role in behavior and specifically in behavioral outcomes following antidepressant treatment. The current results suggest that activation of CREMτ may provide a means to accelerate the therapeutic efficacy of current antidepressant treatment.
转录因子环磷腺苷反应元件结合蛋白（CREB）与抑郁症的病理生理学以及抗抑郁治疗的疗效有关。然而，改变 CREB 水平似乎会对焦虑和抑郁相关行为产生不同的影响，具体取决于所检查的大脑区域。此外，许多 CREB 的操作都会导致其他 CREB 家族蛋白的相应变化，而这些变化的影响在很大程度上被忽视了。为了进一步研究 CREB 在与抑郁相关的行为和抗抑郁反应中的特定区域的重要性，我们使用 Creb(loxP/loxP) 小鼠将 CREB 缺失定位到海马体。在对慢性抗抑郁反应敏感的测定中，新奇诱导的摄食减少程序中，海马体 CREB 缺失并没有改变对慢性抗抑郁治疗的反应。相比之下，海马体 CREB 缺失的小鼠在这项任务中对急性抗抑郁治疗有反应，这种加速反应伴随着海马体神经发生的增加。在 CREB 缺失后观察到 CREB 家族蛋白 cAMP 反应元件调节剂（CREM）的上调。在海马体中过表达 CREM 的激活型异构体 CREMτ 也导致对抗抑郁药的反应加速以及海马体神经发生增加。这是首次证明脑内的 CREMτ 在行为中发挥作用，特别是在抗抑郁治疗后的行为结果中发挥作用。目前的结果表明，激活 CREMτ 可能为加速当前抗抑郁治疗的疗效提供一种手段。
