title: Deletion of GIRK2 Subunit of GIRK Channels Alters the 5-HT1A Receptor-Mediated Signaling and Results in a Depression-Resistant Behavior.
abstract: BACKGROUND
  Targeting dorsal raphe 5-HT1A 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-HT1A receptors were desensitized in GIRK2 knockout mice, as demonstrated by a lower sensitivity of dorsal raphe neurons to the inhibitory effect of the 5-HT1A 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-HT1A receptor-mediated dorsal raphe neuronal activity, becoming alternative therapeutic targets for psychiatric diseases underlying dysfunctional serotonin transmission.
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country UPV/EHU, Leioa, Spain (Drs Llamosas, Bruzos-Cidón, Ugedo, and Torrecilla); Achucarro Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, Bilbao, Spain (Dr Rodríguez); Department of Neuroscience, University of the Basque Country UPV/EHU and CIBERNED, Leioa, Spain (Dr Rodríguez).
authors.forename: Nerea
authors.initials: N
authors.lastname: Llamosas
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country UPV/EHU, Leioa, Spain (Drs Llamosas, Bruzos-Cidón, Ugedo, and Torrecilla); Achucarro Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, Bilbao, Spain (Dr Rodríguez); Department of Neuroscience, University of the Basque Country UPV/EHU and CIBERNED, Leioa, Spain (Dr Rodríguez).
authors.forename: Cristina
authors.initials: C
authors.lastname: Bruzos-Cidón
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country UPV/EHU, Leioa, Spain (Drs Llamosas, Bruzos-Cidón, Ugedo, and Torrecilla); Achucarro Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, Bilbao, Spain (Dr Rodríguez); Department of Neuroscience, University of the Basque Country UPV/EHU and CIBERNED, Leioa, Spain (Dr Rodríguez).
authors.forename: José Julio
authors.initials: JJ
authors.lastname: Rodríguez
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country UPV/EHU, Leioa, Spain (Drs Llamosas, Bruzos-Cidón, Ugedo, and Torrecilla); Achucarro Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, Bilbao, Spain (Dr Rodríguez); Department of Neuroscience, University of the Basque Country UPV/EHU and CIBERNED, Leioa, Spain (Dr Rodríguez).
authors.forename: Luisa
authors.initials: L
authors.lastname: Ugedo
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country UPV/EHU, Leioa, Spain (Drs Llamosas, Bruzos-Cidón, Ugedo, and Torrecilla); Achucarro Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, Bilbao, Spain (Dr Rodríguez); Department of Neuroscience, University of the Basque Country UPV/EHU and CIBERNED, Leioa, Spain (Dr Rodríguez). maria.torrecilla@ehu.es.
authors.forename: Maria
authors.initials: M
authors.lastname: Torrecilla
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D001514:Bee Venoms / Q000494:pharmacology; D015283:Citalopram / Q000494:pharmacology; D003866:Depressive Disorder / Q000188:drug therapy / Q000503:physiopathology*; D004195:Disease Models, Animal; D065847:Dorsal Raphe Nucleus / Q000187:drug effects / Q000503:physiopathology; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000172:deficiency* / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D055500:Resilience, Psychological; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
chemical_list: D018687:Antidepressive Agents, Second-Generation; D001514:Bee Venoms; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C497069:Kcnj6 protein, mouse; D026902:Potassium Channel Blockers; D017366:Serotonin Receptor Agonists; D015283:Citalopram; C029738:tertiapin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin
keywords: 5-HT1A; Dorsal raphe; GIRK; citalopram; electrophysiology