ABSTRACT
Glycogen synthase kinase-3 (GSK3) is a constitutively active protein kinase in brain. Increasing evidence has shown that GSK3 acts as a modulator in the serotonin neurotransmission system, including direct interaction with serotonin 1B (5-HT1B) receptors in a highly selective manner and prominent modulating effect on 5-HT1B receptor activity. In this study, we utilized the serotonin neuron-selective GSK3ß knockout (snGSK3ß-KO) mice to test if GSK3ß in serotonin neurons selectively modulates 5-HT1B autoreceptor activity and function. The snGSK3ß-KO mice were generated by crossbreeding GSK3ß-floxed mice and ePet1-Cre mice. These mice had normal growth and physiological characteristics, similar numbers of tryptophan hydroxylase-2 (TpH2)-expressing serotonin neurons, and the same brain serotonin content as in littermate wild type mice. However, the expression of GSK3ß in snGSK3ß-KO mice was diminished in TpH2-expressing serotonin neurons. Compared to littermate wild type mice, snGSK3ß-KO mice had a reduced response to the 5-HT1B receptor agonist anpirtoline in the regulation of serotonergic neuron firing, cAMP production, and serotonin release, whereas these animals displayed a normal response to the 5-HT1A receptor agonist 8-OH-DPAT. The effect of anpirtoline on the horizontal, center, and vertical activities in the open field test was differentially affected by GSK3ß depletion in serotonin neurons, wherein vertical activity, but not horizontal activity, was significantly altered in snGSK3ß-KO mice. In addition, there was an enhanced anti-immobility response to anpirtoline in the tail suspension test in snGSK3ß-KO mice. Therefore, results of this study demonstrated a serotonin neuron-targeting function of GSK3ß by regulating 5-HT1B autoreceptors, which impacts serotonergic neuron firing, serotonin release, and serotonin-regulated behaviors.
