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Abstract / Description of output
The 5-hydroxytryptamine2C (5-HT)2C receptor is widely implicated in the aetiology of affective and eating disorders as well as regulation of the hypothalamo-pituitary-adrenal axis. Signalling through this receptor is regulated by A-to-I RNA editing, affecting three amino acids in the protein sequence, with unedited transcripts encoding a receptor (INI) that, in vitro, is hyperactive compared with edited isoforms. Targeted alteration (knock-in) of the Htr2c gene to generate 'INI' mice with no alternate splicing, solely expressing the full-length unedited isoform, did not produce an overt metabolic phenotype or altered anxiety behaviour, but did display reduced depressive-like and fear-associated behaviours. INI mice exhibited a hyperactive hypothalamo-pituitary-adrenal axis, with increased nadir plasma corticosterone and corticotrophin-releasing hormone expression in the hypothalamus but responded normally to chronic stress and showed normal circadian activity and activity in a novel environment. The circadian patterns of 5-HT2C receptor mRNA and mbii52, a snoRNA known to regulate RNA editing and RNA splicing of 5-HT2C receptor pre-mRNA, were altered in INI mice compared with wild-type control mice. Moreover, levels of 5-HT1A receptor mRNA were increased in the hippocampus of INI mice. These gene expression changes may underpin the neuroendocrine and behavioural changes observed in INI mice. However, the phenotype of INI mice was not consistent with a globally hyperactive INI receptor encoded by the unedited transcript in the absence of alternate splicing. Hence, the in vivo outcome of RNA editing may be neuronal cell type specific.
Original language | English |
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Pages (from-to) | 3663-3673 |
Number of pages | 11 |
Journal | European Journal of Neuroscience |
Volume | 40 |
Issue number | 11 |
Early online date | 26 Sept 2014 |
DOIs | |
Publication status | Published - Dec 2014 |
Keywords / Materials (for Non-textual outputs)
- anxiety
- depression
- serotonin
- stress
- PRE-MESSENGER-RNA
- ANXIETY-LIKE BEHAVIOR
- SMALL NUCLEOLAR RNAS
- 5-HT2C RECEPTOR
- SEROTONIN 5-HT2C
- PLASMA-CORTICOSTERONE
- NEUTRAL ANTAGONIST
- GENE-EXPRESSION
- REPEATED STRESS
- 2C
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Dive into the research topics of 'Prevention of 5-hydroxytryptamine2C receptor RNA editing and alternate splicing in C57BL/6 mice activates the hypothalamic-pituitary-adrenal axis and alters mood'. Together they form a unique fingerprint.Projects
- 1 Finished
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Functional importance of RNA editing of the 5-HT2C receptor in vivo using a gene-targeting approach
Holmes, M. & Chapman, K.
14/04/07 → 13/03/11
Project: Research