Behavioral and serotonergic consequences of decreasing or increasing hippocampus brain-derived neurotrophic factor protein levels in mice
Behavioral and serotonergic consequences of decreasing or increasing hippocampus brain-derived neurotrophic factor protein levels in mice
复制标题
DOI：
10.1016/j.neuropharm.2008.08.001
复制
发表时间：
2008-11-01
影响因子：
4.7
通讯作者：
Gardier, A. M.
中科院分区：
文献类型：
--
作者：
Deltheil, T.;Guiard, B. P.;Gardier, A. M.
抗抑郁药如选择性5-羟色胺再摄取抑制剂（SSRI）作为5-羟色胺（5-HT）受体的间接激动剂。尽管这些药物在体外能快速阻断血清素转运体（SERTs），但仍需数周的治疗才能观察到临床效果。这个矛盾还没有得到解决。最近的研究已经确定了细胞内信号蛋白和靶基因的修饰，这些修饰可能有助于SSRI的抗抑郁样活性（例如，神经发生和BDNF蛋白水平的增加），并且可能至少部分地解释了它们的长时间延迟作用。尽管这些数据表明5-HT对BDNF编码基因的表达有正向调节作用，但BDNF对脑5-HT神经传递的相互作用仍然缺乏文献记载。为了研究BDNF对血清素能活性的影响，采用双实验策略分析了成年雄性小鼠脑内BDNF减少（策略1）或增加（策略2）对神经化学和行为的影响。(1)在脑BDNF蛋白水平下降一半的杂合BDNF+/-小鼠中，发现基底细胞外5-HT水平（5-HText）的增强导致SERT下调，即海马中SERT再摄取5-HT的能力下降。此外，SSRI帕罗西汀在BDNF+/-小鼠中未能增加海马5-HText，而在野生型幼崽中却产生了强大的作用。因此，BDNF+/-小鼠可被视为5 -羟色胺能抗抑郁药物遗传抗性的动物模型。(2)在野生型BDNF+/+小鼠中，通过脑内微透析和预测分子抗抑郁和抗焦虑样活性的行为范式（分别为强迫游泳试验（FST）和开放场范式（of）），研究了海马内（vHi）注射BDNF （100 ng）联合SSRI的效果。BDNF诱导成人海马5-HText对帕罗西汀反应的快速和短暂增加，这与FST中抗抑郁样活性的增强有关。BDNF的作用被其高亲和力TrkB受体的拮抗剂K252a选择性阻断。[BDNF + SSRI]共给药的神经化学和行为效应之间的相关性表明，其抗抑郁样活性与成人海马中5-HT神经传递的激活有关。BDNF对OF测试中的焦虑样行为也有促进作用，而帕罗西汀可以阻止这种焦虑发生。BDNF发挥后一种作用的机制是什么？令人惊讶的是，通过体内定量微透析的零净通量方法，我们发现野生型小鼠海马内注射BDNF降低了SERT的功能活性，这在BDNF+/-小鼠中观察到。然而，SERT再摄取5-HT能力的下降与WT小鼠海马中基础5-HText的增加无关。有趣的是，原位杂交实验表明，TrkB受体mRNA在成年小鼠海马和中叶背核中表达，这表明海马内注射BDNF的神经化学和行为效应可以调动脑5-HT神经传递的突触前和突触后元件。综上所述，这组实验揭示了在成年小鼠脑BDNF水平（双侧海马内注射）降低（BDNF+/-突变小鼠）或增加（BDNF+/-突变小鼠）后，神经化学和行为反应相对相反。鉴于开发新的抗抑郁药物策略，BDNF与慢性SSRI治疗相结合的综合治疗可以提高现有药物的疗效。(C) 2008 Elsevier Ltd版权所有。
Antidepressants such as Selective Serotonin Reuptake Inhibitors (SSRI) act as indirect agonists of serotonin (5-HT) receptors. Although these drugs produce a rapid blockade of serotonin transporters (SERTs) in vitro, several weeks of treatment are necessary to observe clinical benefits. This paradox has not been solved yet. Recent studies have identified modifications of intracellular signaling proteins and target genes that could contribute to antidepressant-like activity of SSRI (e.g., increases in neurogenesis and BDNF protein levels), and may explain, at least in part, their long delay of action. Although these data suggest a positive regulation of 5-HT on the expression of the gene coding for BDNF, the reciprocal effects of BDNF on brain 5-HT neurotransmission remains poorly documented. To study the impact of BDNF on serotonergic activity, a dual experimental strategy was used to analyze neurochemical and behavioral consequences of its decrease (strategy I) or increase (strategy 2) in the brain of adult male mice. (1) In heterozygous BDNF+/- mice in which brain BDNF protein levels were decreased by half, an enhancement of basal extracellular 5-HT levels (5-HText) that induced a down-regulation of SERT, i.e., a decrease in its capacity to reuptake 5-HT, was found in the hippocampus. In addition, the SSRI paroxetine, failed to increase hippocampal 5-HText in BDNF+/- mice, while it produces robust effects in wild-type littermates. Thus, BDNF+/- mice can be viewed as an animal model of genetic resistance to serotonergic antidepressant drugs. (2) In wild-type BDNF+/+ mice, the effects of intra-hippocampal (vHi) injection of BDNF (100 ng) in combination with a SSRI was examined by using intracerebral microdialysis and behavioral paradigms that predict an antidepressant- and anxiolytic-like activity of a molecule [the forced swim test (FST) and the open field paradigm (OF) respectively]. BDNF induced a rapid and transient increase in paroxetine response on 5-HText in the adult hippocampus, which was correlated with a potentiation of its antidepressant-like activity in the FST. The effects of BDNF were selectively blocked by K252a, an antagonist of its high-affinity TrkB receptor. Such a Correlation between neurochemical and behavioral effects of [BDNF + SSRI] co-administration suggests that its antidepressant-like activity is linked to the activation of 5-HT neurotransmission in the adult hippocampus. BDNF also had a facilitatory effect on anxiety-like behavior in the OF test, and paroxetine prevented this anxiogenesis. What was the mechanism by which BDNF exerted these latter effects? Surprisingly, by using zero net flux method of quantitative microdialysis in vivo, we found that an intra-hippocampal BDNF injection in wild-type mice decreased the functional activity of SERT as observed in BDNF+/- mice. However, the decreased capacity of SERT to reuptake 5-HT was not associated to an increase in basal 5-HText in the hippocampus of WT mice. Interestingly, using in situ hybridization experiments indicated that TrkB receptor mRNA was expressed in the hippocampus and dorsal raphe nucleus in adult mice suggesting that the neurochemical and behavioral effects of intra-hippocampal BDNF injection can mobilize both pre- and post-synaptic elements of the brain 5-HT neurotransmission. Taken together, these set of experiments unveiled a relative opposition of neurochemical and behavioral responses following either a decrease (in BDNF+/- mutant mice) or an increase in brain BDNF levels (bilateral intra-hippocampal injection) in adult mice.In view o developing new antidepressant drug strategy, a poly-therapy combining BDNF with a chronic SSRI treatment could thus improve the efficacy of current medications. (C) 2008 Elsevier Ltd. All rights reserved.