Changes in 5-HT2A -mediated behavior and 5-HT2A - and 5-HT1A receptor binding and expression in conditional brain-derived neurotrophic factor knock-out mice

• Published in: Neuroscience Vol. 169; no. 3; pp. 1007 - 1016
• Main Authors: Klein, A.B, Santini, M.A, Aznar, S, Knudsen, G.M, Rios, M
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.09.2010; Elsevier
• Subjects: 5-HT1A; 5-HT2A; 5-HT2C; Amphetamines - pharmacology; Animals; Autoradiography; BDNF; behavior; Behavior, Animal; Binding Sites; Biological and medical sciences; Brain-Derived Neurotrophic Factor - genetics; Brain-Derived Neurotrophic Factor - metabolism; Frontal Lobe - metabolism; Fundamental and applied biological sciences. Psychology; Hippocampus - metabolism; Mice; Mice, Knockout; Neurology; Neurons - metabolism; Proto-Oncogene Proteins c-fos - metabolism; Radioligand Assay; Receptor, Serotonin, 5-HT1A - metabolism; Receptor, Serotonin, 5-HT2A - physiology; Receptor, Serotonin, 5-HT2C - metabolism; serotonin; Serotonin Plasma Membrane Transport Proteins - metabolism; Serotonin Receptor Agonists - pharmacology; Vertebrates: nervous system and sense organs; DRN; RT; room temperature; 5-HT 1AR; 5-HT receptor 2A; 5-HT 2AR; HTR; 5-HT 2CR; 5-HT receptor 2C; head-twitch response; serotonin; CA1; MAP2; sodium dodecyl sulfate; 5-HT 2A; brain-derived neurotrophic factor; 5-HT 2C; behavior; DOI; tissue equivalents; SDS; BDNF; ESR; 5-HT receptor 1A; cornu ammonis 1 of hippocampus; ear-scratch response; microtubule associated protein 2; dorsal raphe nucleus; (±)-2,5-dimethoxy-4-iodoamphetamine; TE; SERT; TrkB; serotonin transporter; tropomysoin-related kinase B; 5-HT 1A; 5-HT2CR; 5-HT2AR; 5-HT1AR; 5-HT1A; 5-HT2C; 5-HT2A; 5-HT2A serotonin receptor; Serotonin; Rodentia; Vertebrata; Mammalia; 5-HT1A Serotonine receptor; Mouse; Animal; Neurotransmitter; Behavior; Brain derived neurotrophic factor; 5-HT
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2010.05.054

Abstract Changes in brain-derived neurotrophic factor (BDNF) expression have been implicated in the etiology of psychiatric disorders. To investigate pathological mechanisms elicited by perturbed BDNF signaling, we examined mutant mice with central depletion of BDNF (BDNF2L/2LCk-cre ). A severe impairment specific for the serotonin 2A receptor (5-HT2A R) in prefrontal cortex was described previously in these mice. This is of much interest, as 5-HT2A Rs have been linked to neuropsychiatric disorders and anxiety-related behavior. Here we further characterized the serotonin receptor alterations triggered by BDNF depletion. 5-HT2A ([3 H]-MDL100907) and 5-HT1A ([3 H]-WAY100635) receptor autoradiography revealed site-specific alterations in BDNF mutant mice. They exhibited lower 5-HT2A receptor binding in frontal cortex but increased binding in hippocampus. Additionally, 5-HT1A receptor binding was decreased in hippocampus of BDNF mutants, but unchanged in frontal cortex. Molecular analysis indicated corresponding changes in 5-HT2A and 5-HT1A mRNA expression but normal 5-HT2C content in these brain regions in BDNF2L/2LCk-cre mice. We investigated whether the reduction in frontal 5-HT2A R binding was reflected in reduced functional output in two 5-HT2A -receptor mediated behavioral tests, the head-twitch response (HTR) and the ear-scratch response (ESR). BDNF2L/2LCk-cre mutants treated with the 5-HT2A receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) showed a clearly diminished ESR but no differences in HTR compared to wildtypes. These findings illustrate the context-dependent effects of deficient BDNF signaling on the 5-HT receptor system and 5-HT2A -receptor functional output.