RNA splicing and editing modulation of 5-HT(2C) receptor function: relevance to anxiety and aggression in VGV mice

Mol Psychiatry. 2013 Jun;18(6):656-65. doi: 10.1038/mp.2012.171. Epub 2012 Dec 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aggression / physiology*
  • Animals
  • Anxiety / genetics*
  • Bioluminescence Resonance Energy Transfer Techniques
  • Brain / metabolism
  • Defense Mechanisms
  • Disease Models, Animal
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / immunology
  • Glycine / genetics
  • HEK293 Cells
  • Humans
  • Hydroxyindoleacetic Acid / metabolism
  • Interpersonal Relations
  • Mice
  • Mice, Inbred C57BL
  • Mutation / genetics
  • Phenylalanine / analogs & derivatives
  • Phenylalanine / pharmacology
  • Protein Binding / drug effects
  • Protein Binding / genetics
  • Protein Isoforms / genetics
  • RNA Editing / genetics*
  • RNA Precursors / metabolism
  • RNA Splicing / genetics*
  • RNA, Messenger / metabolism
  • Receptor, Serotonin, 5-HT2C / genetics
  • Receptor, Serotonin, 5-HT2C / metabolism*
  • Transfection
  • Ultrasonics
  • Valine / genetics


  • Protein Isoforms
  • RNA Precursors
  • RNA, Messenger
  • Receptor, Serotonin, 5-HT2C
  • phenylalanine methyl ester
  • Phenylalanine
  • Hydroxyindoleacetic Acid
  • Valine
  • Glycine