Deletion of GIRK2 Subunit of GIRK Channels Alters the 5-HT sub(1A) Receptor-Mediated Signaling and Results in a Depression-Resistant Behavior

• Published in: The international journal of neuropsychopharmacology Vol. 18; no. 11
• Main Authors: Llamosas, Nerea, Bruzos-Cidon, Cristina, Rodriguez, Jose Julio, Ugedo, Luisa, Torrecilla, Maria
• Format: Journal Article
• Language: English
• Published: 01.01.2015
• ISSN: 1461-1457; 1469-5111
• DOI: 10.1093/ijnp/pyv051

Background: Targeting dorsal raphe 5-HT sub(1A) receptors, which are coupled to G-protein inwardly rectifying potassium (GIRK) channels, has revealed their contribution not only to behavioral and functional aspects of depression but also to the clinical response to its treatment. Although GIRK channels containing GIRK2 subunits play an important role controlling excitability of several brain areas, their impact on the dorsal raphe activity is still unknown. Thus, the goal of the present study was to investigate the involvement of GIRK2 subunit-containing GIRK channels in depression-related behaviors and physiology of serotonergic neurotransmission. Methods: Behavioral, functional, including in vivo extracellular recordings of dorsal raphe neurons, and neurogenesis studies were carried out in wild-type and GIRK2 mutant mice. Results: Deletion of the GIRK2 subunit promoted a depression-resistant phenotype and determined the behavioral response to the antidepressant citalopram without altering hippocampal neurogenesis. In dorsal raphe neurons of GIRK2 knockout mice, and also using GIRK channel blocker tertiapin-Q, the basal firing rate was higher than that obtained in wild-type animals, although no differences were observed in other firing parameters. 5-HT sub(1A) receptors were desensitized in GIRK2 knockout mice, as demonstrated by a lower sensitivity of dorsal raphe neurons to the inhibitory effect of the 5-HT sub(1A)receptor agonist, 8-OH-DPAT, and the antidepressant citalopram. Conclusions: Our results indicate that GIRK channels formed by GIRK2 subunits determine depression-related behaviors as well as basal and 5-HT sub(1A) receptor-mediated dorsal raphe neuronal activity, becoming alternative therapeutic targets for psychiatric diseases underlying dysfunctional serotonin transmission.