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 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.
Guiard
Bruno P
BP
Université Paris-Sud, EA3544, Faculté de Pharmacie, Chatenay-Malabry, France.
David
Denis J P
DJ
Deltheil
Thierry
T
Chenu
Franck
F
Le Maître
Erwan
E
Renoir
Thibault
T
Leroux-Nicollet
Isabelle
I
Sokoloff
Pierre
P
Lanfumey
Laurence
L
Hamon
Michel
M
Andrews
Anne M
AM
Hen
René
R
Gardier
Alain M
AM
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
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