AP-1 controls the p11-dependent antidepressant response
AP-1 controls the p11-dependent antidepressant response
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DOI：
10.1038/s41380-020-0767-8
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发表时间：
2020-05-21
影响因子：
11
通讯作者：
Greengard, Paul
中科院分区：
文献类型：
--
作者：
Chottekalapanda, Revathy U.;Kalik, Salina;Greengard, Paul
选择性5-羟色胺再摄取抑制剂（SSRIs）是治疗情绪障碍最常用的处方药。虽然SSRI的作用机制仍不清楚，但SSRI被认为通过提高脑中细胞外5-羟色胺水平发挥治疗作用，并重塑抑郁症期间失调的结构和功能改变。为了确定其精确的作用模式，我们测试了这种神经适应性过程是否受到特定基因表达程序的调节。在这里，我们确定了一个转录程序调节激活蛋白-1（AP-1）复合物，形成c-Fos和c-Jun的选择性激活之前的慢性SSRI反应的发作。AP-1转录程序调节关键神经元重塑基因的表达，包括S100 a10（p11），将神经元可塑性与抗抑郁反应联系起来。我们发现，AP-1的功能所需的抗抑郁作用在体内。此外，我们证明了BDNF和FGF 2的神经化学途径，通过MAPK，PI 3 K和JNK级联，调节AP-1功能，介导抗抑郁反应的有益作用。在这里，我们提出了一个连续的分子网络来跟踪抗抑郁药的反应，并提供了一个新的途径，可用于加速或加强抗抑郁药的反应，通过触发神经可塑性。
Selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed drugs for mood disorders. While the mechanism of SSRI action is still unknown, SSRIs are thought to exert therapeutic effects by elevating extracellular serotonin levels in the brain, and remodel the structural and functional alterations dysregulated during depression. To determine their precise mode of action, we tested whether such neuroadaptive processes are modulated by regulation of specific gene expression programs. Here we identify a transcriptional program regulated by activator protein-1 (AP-1) complex, formed by c-Fos and c-Jun that is selectively activated prior to the onset of the chronic SSRI response. The AP-1 transcriptional program modulates the expression of key neuronal remodeling genes, including S100a10 (p11), linking neuronal plasticity to the antidepressant response. We find that AP-1 function is required for the antidepressant effect in vivo. Furthermore, we demonstrate how neurochemical pathways of BDNF and FGF2, through the MAPK, PI3K, and JNK cascades, regulate AP-1 function to mediate the beneficial effects of the antidepressant response. Here we put forth a sequential molecular network to track the antidepressant response and provide a new avenue that could be used to accelerate or potentiate antidepressant responses by triggering neuroplasticity.