Enhanced 5-HT1A receptor-dependent feedback control over dorsal raphe serotonin neurons in the SERT knockout mouse

NEUROPHARMACOLOGY

卷:89

Article

Soiza-Reilly, Mariano^1,2  Goodfellow, Nathalie M.³  Lambe, Evelyn K.^3,4  Commons, Kathryn G.^1,2 

[1] Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dept Anaesthesia, Boston, MA 02115 USA

[3] Univ Toronto, Dept Physiol, Toronto, ON M5S 1A8, Canada

[4] Univ Toronto, Dept Obstet & Gynaecol, Toronto, ON M5S 1A8, Canada

关键词: Serotonin transporter;    Feedback inhibition;    Dorsal raphe nucleus;    Swim stress;    Depressive-like behavior;    Mood disorders;   

DOI  :  10.1016/j.neuropharm.2014.09.017

来源: Elsevier

【 摘 要 】

5-HT1A receptors are widely expressed in the brain and play a critical role in feedback inhibition of serotonin (5-HT) neurons through multiple mechanisms. Yet, it remains poorly understood how these feedback mechanisms, particularly those involving long-range projections, adapt in mood disorders. Here, we examined several aspects of 5-HT1A receptor function in the 5-HT transporter knockout mouse (SERT-KO), a model of vulnerability to stress and mood disorders. We found that in comparison to wildtype (WT) mice, SERT-KO mice had more passive coping in response to acute swim stress and this was accompanied by hypo-activation of medial prefrontal cortex (mPFC) Fos expression. Both of these effects were reversed by systemically blocking 5-HT1A receptors. Ex-vivo electrophysiological experiments showed that 5-HT exerted greater 5-HT1A-mediated inhibitory effects in the mPFC of SERT-KO mice compared to WT. Since 5-HT1A receptors in the mPFC provide a key feedback regulation of the dorsal raphe nucleus (DRN), we used a disinhibition strategy to examined endogenous feedback control of 5-HT neurons. Blocking 5-HT1A receptors disinhibited several fold more 5-HT neurons in the DRN of SERT-KO than in WT mice, revealing the presence of enhanced feedback inhibition of 5-HT neurons in the SERT-KO. Taken together our results indicate that increased stress sensitivity in the SERI-KO is associated with the enhanced capacity of 5-HT1A receptors to inhibit neurons in the mPFC as well as to exert feedback inhibition of DRN 5-HT neurons. (C) 2014 Elsevier Ltd. All rights reserved.

【 授权许可】

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