Brain-derived neurotrophic factor-deficient mice exhibit a hippocampal hyperserotonergic phenotype

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 in...

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Veröffentlicht in:The international journal of neuropsychopharmacology 2008-02, Vol.11 (1), p.79-92
Hauptverfasser: Guiard, Bruno P., David, Denis J. P., Deltheil, Thierry, Chenu, Franck, Le Maître, Erwan, Renoir, Thibault, Leroux-Nicollet, Isabelle, Sokoloff, Pierre, Lanfumey, Laurence, Hamon, Michel, Andrews, Anne M., Hen, René, Gardier, Alain M.
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Sprache:eng
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Zusammenfassung: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 [3H]citalopram-binding-site density in the CA3 subregion of the ventral hippocampus and a significant reduction in [3H]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.
ISSN:1461-1457
1469-5111
DOI:10.1017/S1461145707007857