Ribosomal protein S6 kinase 1 signaling in prefrontal cortex controls depressive behavior
Ribosomal protein S6 kinase 1 signaling in prefrontal cortex controls depressive behavior
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DOI：
10.1073/pnas.1505289112
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发表时间：
2015-05-12
影响因子：
11.1
通讯作者：
Duman, Ronald S.
中科院分区：
文献类型：
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作者：
Dwyer, Jason M.;Maldonado-Aviles, Jaime G.;Duman, Ronald S.
目前对重度抑郁症（MDD）的治疗存在时间滞后，并且对大量患者无效。新型药物疗法的开发需要全面了解导致 MDD 病理生理学的分子事件。最近的证据表明突触蛋白的异常活动是一个关键的影响因素。在本研究中，我们使用病毒介导的基因转移来靶向雷帕霉素复合物 1 (mTORC1) 机械靶标下游的活性依赖性突触蛋白合成的关键介质，即 p70 S6 激酶 1 (S6K1)。将两种 S6K1 突变体（组成型活性或显性失活）靶向递送至大鼠内侧前额皮质 (mPFC)，从而可以控制 mTORC1/S6K1 翻译途径。我们的结果表明，mPFC 中 S6K1 表达的增加在强迫游泳测试中产生抗抑郁作用，而不改变运动活动。此外，mPFC中活性S6K1的表达阻断了慢性应激引起的快感缺乏，导致应激恢复状态。这种抗抑郁反应与 S6K1 活性增强引起的神经元复杂性增加有关。相反，mPFC 中显性失活的 S6K1 表达会导致强迫游泳测试中的抑郁行为，并且在没有慢性压力暴露的情况下足以引起快感缺乏。总之，这些数据证明了 S6K1 活性在抑郁行为中的关键作用，并表明 mTORC1 下游通路可能是 MDD 病理生理学和治疗的基础。
Current treatments for major depressive disorder (MDD) have a time lag and are ineffective for a large number of patients. Development of novel pharmacological therapies requires a comprehensive understanding of the molecular events that contribute to MDD pathophysiology. Recent evidence points toward aberrant activity of synaptic proteins as a critical contributing factor. In the present studies, we used viral-mediated gene transfer to target a key mediator of activity-dependent synaptic protein synthesis downstream of mechanistic target of rapamycin complex 1 (mTORC1) known as p70 S6 kinase 1 (S6K1). Targeted delivery of two mutants of S6K1, constitutively active or dominant-negative, to the medial prefrontal cortex (mPFC) of rats allowed control of the mTORC1/S6K1 translational pathway. Our results demonstrate that increased expression of S6K1 in the mPFC produces antidepressant effects in the forced swim test without altering locomotor activity. Moreover, expression of active S6K1 in the mPFC blocked the anhedonia caused by chronic stress, resulting in a state of stress resilience. This antidepressant response was associated with increased neuronal complexity caused by enhanced S6K1 activity. Conversely, expression of dominant-negative S6K1 in the mPFC resulted in prodepressive behavior in the forced swim test and was sufficient to cause anhedonia in the absence of chronic stress exposure. Together, these data demonstrate a critical role for S6K1 activity in depressive behaviors, and suggest that pathways downstream of mTORC1 may underlie the pathophysiology and treatment of MDD.