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-HT_1A autoreceptors (5-HT_1AARs). Enhanced 5-HT_1AAR 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_1AAR functioning. To elucidate the mechanisms underlying 5-HT_1AAR 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 < 0.001) whereas the maximal response, proportional to the 5-HT_1AAR 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-HT_1AARs to GIRK channels in Tph2^-/- mice without a concomitant increase in 5-HT_1AARs 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-HT_1AAR 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_1AAR density and depression in clinical imaging studies.