Increased functional coupling of 5-HT_1A autoreceptors to GIRK channels in Tph2^-/- mice

Firing activity of serotonergic neurons is under regulatory control by somatodendritic 5-HT1A 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-HT1A 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-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-HT(1A)AR 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-gamma-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 alpha(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. (C) 2017 Elsevier B.V. and ECNP. All rights reserved.