Norifumi Shioda, Yoshiki Imai, Yasushi Yabuki, Wataru Sugimoto, Kouya Yamaguchi, Yanyan Wang, Takatoshi Hikida, Toshikuni Sasaoka, Michihiro Mieda, and Kohji Fukunaga. Dopamine D2L Receptor Deficiency Causes Stress Vulnerability through 5-HT1A Receptor Dysfunction in Serotonergic Neurons.
Journal of Neuroscience. in press.
doi: 10.1523/JNEUROSCI.0079-19.2019.
Mental disorders are caused by genetic and environmental factors. We here show that deficiency of an isoform of dopamine D2 receptor (D2R), D2LR, causes stress vulnerability in mouse. This occurs through dysfunction of serotonin (5-hydroxytryptamine, 5-HT) 1A receptor (5-HT1AR) on serotonergic neurons in the mouse brain. Exposure to forced swim stress significantly increased anxiety- and depressive-like behaviors in D2LR knockout (D2LR-KO) male mice as compared with wild-type mice. Treatment with 8-OH-DPAT, a 5-HT1AR agonist, failed to alleviate the stress-induced behaviors in D2LR-KO mice. In forced swim-stressed D2LR-KO mice, 5-HT efflux in the medial prefrontal cortex was elevated and the expression of genes related to 5-HT levels was up-regulated by the transcription factor PET1 in the dorsal raphe nucleus. Notably, D2LR formed a heteromer with 5-HT1AR in serotonergic neurons, thereby suppressing 5-HT1AR–activated G-protein–activated inwardly rectifying potassium (GIRK) conductance in D2LR-KO serotonergic neurons. Finally, D2LR overexpression in serotonergic neurons in the dorsal raphe nucleus alleviated stress vulnerability observed in D2LR-KO mice. Taken together, we conclude that disruption of the negative feedback regulation by the D2LR/5-HT1A heteromer causes stress vulnerability.
Figure
D2LR deficiency causes collapse of the negative feedback control of the D2LR/5-HT1AR inhibitory G-protein–coupled heteromer in serotonergic neurons. (1) Stress-induced depolarization triggers Ca2+ influx through L-type voltage-dependent calcium channels (L-VDCC) and N-methyl-D-aspartate receptors (NMDA-R). (2) The Ca2+ influx leads to activation of numerous kinase pathways, resulting in activation of a transcription factor PET1, which is a key modulator of 5-HT synthesis. (3) PET1 activation increases Tph2, Sert, and Gchfr transcript levels, increasing 5-HT synthesis and extracellular release. (4) Extracellular 5-HT activates the D2LR/5-HT1AR heteromer, and induces Galphai activation, inhibition of adenylyl cyclase (AC), and activation of GIRK currents. This results in decreased firing rate of serotonergic neurons and limits 5-HT release. In D2LR deficiency, 5-HT1AR cannot properly function against stress because of the collapse of the negative feedback mechanism, thereby eliciting excessive 5-HT release and stress vulnerability.
