1A autoreceptors to GIRK channels in Tph2 -/- mice

摘要

Abstract Firing activity of serotonergic neurons is under regulatory control by somatodendritic 5-HT 1A autoreceptors (5-HT 1A ARs). Enhanced 5-HT 1A AR 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-HT 1A agonist-induced inhibition of serotonergic neuron firing and thus represents a unique animal model of enhanced 5-HT 1A AR functioning. To elucidate the mechanisms underlying 5-HT 1A AR supersensitivity in Tph2 -/- mice, we characterized the activation of G protein-coupled inwardly-rectifying potassium (GIRK) conductance by the 5-HT 1A 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 1A AR number, was not different ( p = 0.42) com p ared 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-HT 1A ARs to GIRK channels in Tph2 -/- mice without a concomitant increase in 5-HT 1A ARs and/or GIRK channel density. In addition, no changes were found in α 1 -adrenergic facilitation of firing ( p = 0.72) indicating lack of adaptive changes Tph2 -/- mice. 5-HT 1A AR 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-HT 1A AR density and depression in clinical imaging studies.