Increased functional coupling of 5-HT1A autoreceptors to GIRK channels in Tph2-/- mice.
Eur Neuropsychopharmacol
; 27(12): 1258-1267, 2017 12.
Article
em En
| MEDLINE
| ID: mdl-29126768
ABSTRACT
Firing activity of serotonergic neurons is under regulatory control by somatodendritic 5-HT1A autoreceptors (5-HT1AARs). Enhanced 5-HT1AAR functioning may cause decreased serotonergic signaling in brain and has thereby been implicated in the etiology of mood and anxiety disorders. Tryptophan hydroxylase-2 knockout (Tph2-/-) mice exhibit sensitization of 5-HT1A agonist-induced inhibition of serotonergic neuron firing and thus represents a unique animal model of enhanced 5-HT1AAR functioning. To elucidate the mechanisms underlying 5-HT1AAR supersensitivity in Tph2-/- mice, we characterized the activation of G protein-coupled inwardly-rectifying potassium (GIRK) conductance by the 5-HT1A receptor agonist 5-carboxamidotryptamine using whole-cell recordings from serotonergic neurons in dorsal raphe nucleus. Tph2-/- mice exhibited a mean twofold leftward shift of the agonist concentration-response curve (p < 0.001) whereas the maximal response, proportional to the 5-HT1AAR number, was not different (p = 0.42) compared to Tph2+/- and Tph2+/+ littermates. No differences were found in the basal inwardly-rectifying potassium conductance, determined in the absence of agonist, (p = 0.80) nor in total GIRK conductance activated by intracellular application of GTP-γ-S (p = 0.69). These findings indicate increased functional coupling of 5-HT1AARs to GIRK channels in Tph2-/- mice without a concomitant increase in 5-HT1AARs and/or GIRK channel density. In addition, no changes were found in α1-adrenergic facilitation of firing (p = 0.72) indicating lack of adaptive changes Tph2-/- mice. 5-HT1AAR supersensitivity may represents a previously unrecognized cause of serotonergic system hypofunction and associated disorders and provides a possible explanation for conflicting results on the correlation between 5-HT1AAR density and depression in clinical imaging studies.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Triptofano Hidroxilase
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Regulação da Expressão Gênica
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Receptor 5-HT1A de Serotonina
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Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G
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Neurônios Serotoninérgicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Eur Neuropsychopharmacol
Ano de publicação:
2017
Tipo de documento:
Article