The Role of HIF-1 in Neurogenic and Behavior Responses to Antidepressants.

描述（由申请人提供）：重度抑郁症（MDD）是一种与显著发病率和死亡率相关的衰弱性心境障碍。不同类别的抗抑郁药通过独特的机制作用于特定但不同的神经递质系统。值得注意的是，糖原合成酶激酶-3（GSK-3）的抑制是不同类型抗抑郁药以及情绪稳定剂治疗的常见分子结果。我们已经提出了这样的假设，GSK-3是锂的分子靶点，锂是一种情绪稳定剂，并调节几种抗抑郁药敏感的行为。GSK-3参与多种细胞内途径，包括Wnt和胰岛素信号传导。背景下 在激活Wnt信号的过程中，GSK-3被抑制，导致转录因子β-连环蛋白的积累。因此，锂通过抑制GSK-3来重现Wnt/β-连环蛋白信号传导。在我们的研究过程中，我们发现了几种抗抑郁药敏感的行为，这些行为同样受到锂的影响。这是一个有趣的平行，锂和抗抑郁药抑制GSK-3和影响小鼠的行为类似。事实上，GSK-3b的杂合丢失模拟了抗抑郁药对这些测试的影响。GSK-3下游与抗抑郁治疗的行为效应相关的关键分子效应物尚未确定。这项提议将检验一个假设，即最近发现的缺氧诱导因子1 <$a（Hif-1a）是Wnt/<$-连环蛋白信号转导的调节剂，是锂和抗抑郁药丙咪嗪和氟西汀对行为的影响所必需的。值得注意的是，锂和抗抑郁药作为一种常见的细胞相关物也能增强成人神经发生！增强海马神经发生已被提出作为抗抑郁药和情绪稳定治疗反应的一个组成部分，但关于抗抑郁药对神经发生的影响知之甚少。Wnt/β-连环蛋白信号传导对于海马中的成年神经发生是至关重要的。在最近的合作中，我们发现Hif-1a调节胚胎干细胞和神经干/祖细胞中的Wnt/β-catenin转录，但不调节分化的神经元。神经元特异性缺失Hif-1a导致小鼠海马中严重的成人神经发生缺陷。值得注意的是，Hif-1a KO小鼠中的神经发生缺陷可以通过抑制GSK-3或稳定<$-连环蛋白来挽救，这两者都激活下游Wnt信号传导。这些新的发现证明了在神经发生中需要Hif-1a，以及NSC特有的调节Wnt/β-catenin介导的转录的新机制。这项提议将检验Hif 1a是抗抑郁药诱导的神经发生增强所必需的假设，以及抗抑郁药直接作用于NSC的假设。该提案将确定Hif-1a缺失对Wnt/β-catenin信号传导的影响，以及抗抑郁药在分子、细胞和行为水平上拯救Hif-1a KO表型的能力。缺氧信号与情绪稳定剂和抗抑郁药的作用之间的新联系可能会导致更好地理解情感障碍和治疗情感障碍的新方法。

DESCRIPTION (provided by applicant): Major Depressive Disorder (MDD) is a debilitating mood disorder associated with significant morbidity and mortality. Different classes of antidepressants act through unique mechanisms on specific, yet distinct neurotransmitter systems. It is a noteworthy coincidence that inhibition of glycogen synthase kinase-3 (GSK-3) is a common molecular consequence of treatment with diverse classes of antidepressants as well as mood stabilizers. We have forwarded the hypothesis that GSK-3 is the molecular target of lithium, a mood stabilizer, and modulates several antidepressant-sensitive behaviors. GSK-3 participates in multiple intracellular pathways including Wnt and insulin signaling. In the context of active Wnt signaling, GSK-3 is inhibited, resulting in the accumulation of the transcription factor ¿-catenin. Thus lithium recapitulates Wnt/¿-catenin signaling by inhibiting GSK-3. During the course of our studies, we found several antidepressant-sensitive behaviors that were similarly affected by lithium. It is an intriguing parallel that lithium and antidepressants inhibi GSK-3 and affect mouse behaviors similarly. Indeed, heterozygous loss of GSK-3b mimicked the effect of antidepressants on these tests. The critical molecular effectors(s) downstream of GSK-3, relevant to the behavioral effects of antidepressant treatment have yet to be identified. This proposal will test the hypothesis that hypoxia-induced factor 1¿ (Hif-1a), recently discovered as a modulator of Wnt/¿-catenin signaling, is required for the effects of lithium and the antidepressants, imipramine and fluoxetine on behavior. Remarkably, lithium and antidepressants also enhance adult neurogenesis as a common cellular correlate! Enhanced hippocampal neurogenesis has been proposed as an integral component of the response to antidepressant and mood stabilizing therapy, yet little is known regarding the effect of antidepressants on neurogenesis. Wnt/¿-catenin signaling is critical for adult neurogenesis in the hippocampus. In a recent collaboration we found that Hif-1a regulates Wnt/¿-catenin transcription in embryonic stem cells and neural stem/progenitor cells but not in differentiated neurons. Neuron-specific deletion of Hif-1a in mice results in a severe adult neurogenesis defect in the hippocampus. Remarkably, the neurogenesis defect in Hif-1a KO mice can be rescued by inhibition of GSK-3 or stabilization of ¿-catenin, both of which activate downstream Wnt signaling. These novel findings demonstrate a requirement for Hif-1a in neurogenesis and a novel mechanism of regulating Wnt/¿-catenin mediated transcription unique to NSCs. This proposal will test the hypothesis that Hif1a is required for antidepressant-induced enhancement of neurogenesis and that antidepressants act directly on NSCs. This proposal will determine the impact of Hif-1a deletion on Wnt/¿-catenin signaling and the ability antidepressants to rescue Hif-1a KO phenotypes at the molecular, cellular and behavior level. A new connection between hypoxia signaling and the actions of mood stabilizers and antidepressants could lead to a better understanding of and new approaches for the treatment of affective disorders.