RNA splicing and editing modulation of 5-HT2C receptor function: relevance to anxiety and aggression in VGV mice
In: Molecular psychiatry, Jg. 18 (2013), Heft 6, S. 656-665
Online
academicJournal
- print; 10; 62 ref
Zugriff:
Changes in serotonin2C 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 3H-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.
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RNA splicing and editing modulation of 5-HT2C receptor function: relevance to anxiety and aggression in VGV mice
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Autor/in / Beteiligte Person: | MARTIN, Cbp ; RAMOND, F ; MADJAR, J. J ; MONGEAU, R ; FARRINGTON, D. T ; AGUIAR, A. S ; CHEVARIN, C ; BERTHIAU, A.-S ; CAUSSANEL, S ; LANFUMEY, L ; HERRICK-DAVIS, K ; HAMON, M |
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Zeitschrift: | Molecular psychiatry, Jg. 18 (2013), Heft 6, S. 656-665 |
Veröffentlichung: | Basingstoke: Nature Publishing Group, 2013 |
Medientyp: | academicJournal |
Umfang: | print; 10; 62 ref |
ISSN: | 1359-4184 (print) |
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