title: Brain-derived neurotrophic factor-deficient mice exhibit a hippocampal hyperserotonergic phenotype.
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.
authors.affiliation: Université Paris-Sud, EA3544, Faculté de Pharmacie, Chatenay-Malabry, France.
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Guiard
authors.forename: Denis J P
authors.initials: DJ
authors.lastname: David
authors.forename: Thierry
authors.initials: T
authors.lastname: Deltheil
authors.forename: Franck
authors.initials: F
authors.lastname: Chenu
authors.forename: Erwan
authors.initials: E
authors.lastname: Le Maître
authors.forename: Thibault
authors.initials: T
authors.lastname: Renoir
authors.forename: Isabelle
authors.initials: I
authors.lastname: Leroux-Nicollet
authors.forename: Pierre
authors.initials: P
authors.lastname: Sokoloff
authors.forename: Laurence
authors.initials: L
authors.lastname: Lanfumey
authors.forename: Michel
authors.initials: M
authors.lastname: Hamon
authors.forename: Anne M
authors.initials: AM
authors.lastname: Andrews
authors.forename: René
authors.initials: R
authors.lastname: Hen
authors.forename: Alain M
authors.initials: AM
authors.lastname: Gardier
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D001923:Brain Chemistry / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency* / Q000235:genetics*; D015283:Citalopram; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis; D017374:Paroxetine; D010641:Phenotype; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology
chemical_list: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D019208:Brain-Derived Neurotrophic Factor; D015283:Citalopram; D017374:Paroxetine; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors