BDNF overexpression in mouse hippocampal astrocytes promotes local neurogenesis and elicits anxiolytic-like activities.
BDNF overexpression in mouse hippocampal astrocytes promotes local neurogenesis and elicits anxiolytic-like activities.
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DOI：
10.1038/tp.2013.30
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发表时间：
2013-04-30
影响因子：
6.8
通讯作者：
Guiard BP
中科院分区：
文献类型：
--
作者：
Quesseveur G;David DJ;Gaillard MC;Pla P;Wu MV;Nguyen HT;Nicolas V;Auregan G;David I;Dranovsky A;Hantraye P;Hen R;Gardier AM;Déglon N;Guiard BP
选择性5-羟色胺（5-HT）再摄取抑制剂（SSRIs）的治疗活性依赖于突触前和突触后水平的长期适应。持续给予SSRIs增加了对中缝背核中抑制性5-HT 1A自身受体功能性脱敏反应的多巴胺能神经传递。在神经末梢如海马，5-HT可用性的增强增加了脑源性神经营养因子（BDNF）的合成和信号传导，这是刺激成人神经发生的主要事件。在生理条件下，BDNF将在神经元中以功能相关水平表达。然而，最近观察到SSRIs上调星形胶质细胞原代培养物中的BDNF mRNA，这强烈表明抗抑郁药物的治疗活性可能是由于这种细胞类型中BDNF合成的增加。在这项研究中，通过在星形胶质细胞中过表达BDNF，我们平衡了星形胶质细胞和神经元BDNF之间的比例，从而提高了这种操作可能对转染小鼠的抗焦虑/抗抑郁样活性产生积极影响的可能性。我们的研究结果表明，BDNF在海马星形胶质细胞的过度表达产生抗焦虑/抗抑郁样活性的新奇抑制喂养与海马神经发生的刺激，而它并没有加强的SSRI氟西汀对这些参数的影响。此外，过度表达BDNF揭示了氟西汀在高架十字迷宫中的抗焦虑样活性，同时响应于5-HT 1A自身受体的钝化下调而减弱5-HT神经传递。这些结果强调了海马星形胶质细胞在BDNF合成中的原始作用，BDNF可以通过神经发生依赖性和非依赖性机制来调节抗焦虑样反应的不同方面。
The therapeutic activity of selective serotonin (5-HT) reuptake inhibitors (SSRIs) relies on long-term adaptation at pre- and post-synaptic levels. The sustained administration of SSRIs increases the serotonergic neurotransmission in response to a functional desensitization of the inhibitory 5-HT1A autoreceptor in the dorsal raphe. At nerve terminal such as the hippocampus, the enhancement of 5-HT availability increases brain-derived neurotrophic factor (BDNF) synthesis and signaling, a major event in the stimulation of adult neurogenesis. In physiological conditions, BDNF would be expressed at functionally relevant levels in neurons. However, the recent observation that SSRIs upregulate BDNF mRNA in primary cultures of astrocytes strongly suggest that the therapeutic activity of antidepressant drugs might result from an increase in BDNF synthesis in this cell type. In this study, by overexpressing BDNF in astrocytes, we balanced the ratio between astrocytic and neuronal BDNF raising the possibility that such manipulation could positively reverberate on anxiolytic-/antidepressant-like activities in transfected mice. Our results indicate that BDNF overexpression in hippocampal astrocytes produced anxiolytic-/antidepressant-like activity in the novelty suppressed feeding in relation with the stimulation of hippocampal neurogenesis whereas it did not potentiate the effects of the SSRI fluoxetine on these parameters. Moreover, overexpressing BDNF revealed the anxiolytic-like activity of fluoxetine in the elevated plus maze while attenuating 5-HT neurotransmission in response to a blunted downregulation of the 5-HT1A autoreceptor. These results emphasize an original role of hippocampal astrocytes in the synthesis of BDNF, which can act through neurogenesis-dependent and -independent mechanisms to regulate different facets of anxiolytic-like responses.
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DOI：
10.1017/s1461145709000017
发表时间：
2009-08-01
影响因子：
4.8
作者：
Deltheil, Thierry;Tanaka, Kenji;Gardier, Alain M.
通讯作者：
Gardier, Alain M.
影响因子：
4.7
作者：
Guiard, BP;Froger, N;Lanfumey, L
通讯作者：
Lanfumey, L
影响因子：
4.2
作者：
Inazu, M;Takeda, H;Matsumiya, T
通讯作者：
Matsumiya, T
影响因子：
3.4
作者：
Allaman, Igor;Fiumelli, Hubert;Martin, Jean-Luc
通讯作者：
Martin, Jean-Luc
影响因子：
6.2
作者：
Colin, Angelique;Faideau, Mathilde;Deglon, Nicole
通讯作者：
Deglon, Nicole