title: RNA splicing and editing modulation of 5-HT(2C) receptor function: relevance to anxiety and aggression in VGV mice.
abstract: Changes in serotonin(2C) receptor (5-HTR2c) editing, splicing and density were found in conditions such as depression and suicide, but mechanisms explaining the changes in 5-HTR2c function are unknown. Thus, mice expressing only the fully edited VGV isoform of 5-HTR2c, in which clinically relevant behavioral changes are associated with alterations in splicing and receptor density, were studied. VGV mice displayed enhanced anxiety-like behavior in response to a preferential 5-HTR2c agonist in the social interaction test. Nearly half of interactions between pairs of VGV congeners consisted of fighting behaviors, whereas no fighting occurred in wild-type (WT) mice. VGV mice also exhibited a striking increase in freezing behaviors in reaction to an innately aversive ultrasonic stimulus. This behavioral phenotype occurred in conjunction with decreased brain 5-HT turnover during stress. These functional data were put in relation with the 5-HTR2c mRNA splicing process generating a truncated protein (5-HTR2c-Tr) in addition to the full-length receptor (5-HTR2c-Fl). 5-HTR2c-Tr mRNA was less abundant in many brain regions of VGV mice, which concomitantly had more 5-HTR2c than WT mice. Fluorescence resonance energy transfer and bioluminescence resonance energy transfer studies in transfected living HEK293T cells showed that 5-HTR2c-Tr interacts with 5-HTR2c-Fl. The 5-HTR2c-Tr was localized in the endoplasmic reticulum where it retained 5-HTR2c-Fl, preventing the latter to reach the plasma membrane. Consequently, 5-HTR2c-Tr decreased (3)H-mesulergine binding to 5-HTR2c-Fl at the plasma membrane in a concentration-dependent manner and more strongly with edited 5-HTR2c-Fl. These results suggest that 5-HTR2c pre-mRNA editing and splicing are entwined processes determining increased 5-HTR2c levels in pathological conditions through a deficit in 5-HTR2c-Tr.
authors.affiliation: INSERM U894, Centre de Psychiatrie et de Neuroscience, UPMC, Fac. Med. Pierre and Marie Curie, Site Pitié-Salpêtrière, Paris, France.
authors.forename: C B P
authors.initials: CB
authors.lastname: Martin
authors.forename: F
authors.initials: F
authors.lastname: Ramond
authors.forename: D T
authors.initials: DT
authors.lastname: Farrington
authors.forename: A S
authors.initials: AS
authors.lastname: Aguiar
authors.forename: C
authors.initials: C
authors.lastname: Chevarin
authors.forename: A-S
authors.initials: AS
authors.lastname: Berthiau
authors.forename: S
authors.initials: S
authors.lastname: Caussanel
authors.forename: L
authors.initials: L
authors.lastname: Lanfumey
authors.forename: K
authors.initials: K
authors.lastname: Herrick-Davis
authors.forename: M
authors.initials: M
authors.lastname: Hamon
authors.forename: J J
authors.initials: JJ
authors.lastname: Madjar
authors.forename: R
authors.initials: R
authors.lastname: Mongeau
mesh_terms: D000374:Aggression / Q000502:physiology*; D000818:Animals; D001007:Anxiety / Q000235:genetics*; D060807:Bioluminescence Resonance Energy Transfer Techniques; D001921:Brain / Q000378:metabolism; D003674:Defense Mechanisms; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D005998:Glycine / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007398:Interpersonal Relations; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics; D017393:RNA Editing / Q000235:genetics*; D012322:RNA Precursors / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014465:Ultrasonics; D014633:Valine / Q000235:genetics
chemical_list: D020033:Protein Isoforms; D012322:RNA Precursors; D012333:RNA, Messenger; D044405:Receptor, Serotonin, 5-HT2C; C034515:phenylalanine methyl ester; D010649:Phenylalanine; D006897:Hydroxyindoleacetic Acid; D014633:Valine; D005998:Glycine