Brain-derived neurotrophic factor-deficient mice exhibit a hippocampal hyperserotonergic phenotype
Brain-derived neurotrophic factor-deficient mice exhibit a hippocampal hyperserotonergic phenotype
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DOI：
10.1017/s1461145707007857
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发表时间：
2008-02-01
影响因子：
4.8
通讯作者：
Gardier, Alain M.
中科院分区：
文献类型：
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作者：
Guiard, Bruno P.;David, Denis J. P.;Gardier, Alain M.
越来越多的证据支持脑源性神经营养因子(BDNF)参与情绪障碍和抗抑郁药物的作用机制。然而，BDNF和5-羟色胺能信号之间的关系还知之甚少。利用杂合突变BDNF+/-小鼠，观察BDNF对大鼠海马5-羟色胺(5-HT)系统和5-羟色胺转运体(SERT)活性的影响。BDNF+/-杂合子小鼠海马区基础细胞外5-羟色胺水平升高，重摄取能力降低。与这些结果一致的是，选择性5-羟色胺再摄取抑制剂帕罗西汀未能增加BDNF+/-小鼠海马区细胞外5-羟色胺的水平，但在野生型小鼠中产生了强劲的效果。利用体外放射自显影和突触体技术，我们研究了BDNF+/-小鼠5-羟色胺重摄取减弱的原因。腹侧海马CA3区[H-3]西酞普兰结合部位密度显著降低，突触体内[H-3]5-羟色胺摄取显著减少，主要表现为SERT功能下降。然而，5-HT1A自身受体在BDNF+/-小鼠中并不脱敏。这些结果提供了证据，即BDNF的结构性减少调节了海马区SERT功能的重摄取。
Growing evidence supports the involvement of brain-derived neurotrophic factor (BDNF) in mood disorders and the mechanism of action of antidepressant drugs. However, the relationship between BDNF and serotonergic signalling is poorly understood. Heterozygous mutants BDNF +/- mice were utilized to investigate the influence of BDNF on the serotonin (5-HT) system and the activity of the serotonin transporter (SERT) in the hippocampus. The zero net flux method of quantitative microdialysis revealed that BDNF +/- heterozygous mice have increased basal extracellular 5-HT levels in the hippocampus and decreased 5-HT reuptake capacity. In keeping with these results, the selective serotonin reuptake inhibitor paroxetine failed to increase hippocampal extracellular 5-HT levels in BDNF +/- mice while it produced robust effects in wild-type littermates. Using in-vitro autoradiography and synaptosome techniques, we investigated the causes of attenuated 5-HT reuptake in BDNF +/- mice. A significant decrease in [H-3]citalopram-binding-site density in the CA3 subregion of the ventral hippocampus and a significant reduction-in [H-3]5-HT uptake in hippocampal synaptosomes, revealed mainly a decrease in SERT function. However, 5-HT1A autoreceptors were not desensitized in BDNF +/- mice. These results provide evidence that constitutive reductions in BDNF modulate SERT function reuptake in the hippocampus.