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Thyrotropin-Releasing Hormone Receptor 1-Deficient Mice Display Increased Depression and Anxiety-Like Behavior

Omeros Corporation, Seattle, Washington 98101

Address all correspondence and requests for reprints to: Hongkui Zeng or John E. Bergmann, Omeros Corp., 1420 Fifth Avenue, Suite 2600, Seattle, Washington 98101. E-mail: hongkuiz{at}alleninstitute.org or jbergmann{at}omeros.com.

TRH is a neuropeptide with a variety of hormonal and neurotransmitter/neuromodulator functions. In particular, TRH has pronounced acute antidepressant effects in both humans and animals and has been implicated in the mediation of the effects of other antidepressive therapies. Two G protein-coupled receptors, TRH receptor 1 (TRH-R1) and TRH-R2, have been identified. Here we report the generation and phenotypic characterization of mice deficient in TRH-R1. The TRH-R1 knockout mice have central hypothyroidism and mild hyperglycemia but exhibit normal growth and development and normal body weight and food intake. Behaviorally, the TRH-R1 knockout mice display increased anxiety and depression levels while behaving normally in a number of other aspects examined. These results provide the first direct evidence that the endogenous TRH system is involved in mood regulation, and this function is carried out through TRH-R1-mediated neural pathways.