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  • The International Journal of Neuropsychopharmacology, Volume 11, Issue 1
  • February 2008, pp. 79-92

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

  • Bruno P. Guiard (a1), Denis J. P. David (a1), Thierry Deltheil (a1), Franck Chenu (a2), Erwan Le Maître (a3), Thibault Renoir (a4), Isabelle Leroux-Nicollet (a3), Pierre Sokoloff (a5), Laurence Lanfumey (a4), Michel Hamon (a4), Anne M. Andrews (a6), René Hen (a7) and Alain M. Gardier (a1)
  • DOI: http://dx.doi.org/10.1017/S1461145707007857
  • Published online: 11 June 2007
Abstract
Abstract

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.

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Corresponding author
Address for correspondence: Professor A. Gardier, Université Paris-Sud – Faculté de Pharmacie, Laboratoire de NeuropharmacologieEA3544, Chatenay-Malabry cedex, F92296, France. Tel.: +33 1 46 83 53 61Fax: +33 1 46 83 53 55E-mail: alain.gardier@u-psud.fr
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The International Journal of Neuropsychopharmacology
  • ISSN: 1461-1457
  • EISSN: 1469-5111
  • URL: /core/journals/the-international-journal-of-neuropsychopharmacology
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