The International Journal of Neuropsychopharmacology

Research Article

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

Bruno P. Guiarda1, Denis J. P. Davida1, Thierry Deltheila1, Franck Chenua2, Erwan Le Maîtrea3, Thibault Renoira4, Isabelle Leroux-Nicolleta3, Pierre Sokoloffa5, Laurence Lanfumeya4, Michel Hamona4, Anne M. Andrewsa6, René Hena7 and Alain M. Gardiera1 c1

a1 Université Paris-Sud, EA3544, Faculté de Pharmacie, Chatenay-Malabry, France

a2 Laboratoire de Pharmacologie de l'anxiété et de la dépression EA3256, Faculté de médecine, Nantes, France

a3 FRE 2735 CNRS, IFRMP 23, UFR de Médecine et de Pharmacie, Rouen, France

a4 INSERM UMR 677, Faculté de Médecine Pitié-Salpêtrière, Paris, France

a5 INSERM, Unité de Neurobiologie et Pharmacologie Moléculaire, U573, Centre Paul Broca, Paris, France

a6 Department of Veterinary and Biomedical Sciences, Penn State Neuroscience Institute, The Pennsylvania State University, PA, USA

a7 Center for Neurobiology and Behavior, Columbia University, New York, NY, USA

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.

(Received December 28 2006)

(Reviewed February 06 2007)

(Revised April 05 2007)

(Accepted April 19 2007)

(Online publication June 11 2007)

Correspondence:

c1 Address for correspondence: Professor A. Gardier, Université Paris-Sud – Faculté de Pharmacie, Laboratoire de Neuropharmacologie EA3544, Chatenay-Malabry cedex, F92296, France. Tel.: +33 1 46 83 53 61 Fax: +33 1 46 83 53 55 E-mail: alain.gardier@u-psud.fr