The Journal of biological chemistry 2018 02 15() pii 10.1074/jbc.RA117.000618
Abelson helper integration site 1 (AHI1) is associated with several neuropsychiatric and brain developmental disorders such as schizophrenia, depression, autism, and Joubert syndrome.deficiency in mice leads to behaviors typical of depression. However, the mechanisms by which AHI1 regulates behavior remain to be elucidated. Here, we found that down-regulation of expression of the rate-limiting enzyme in dopamine biosynthesis, tyrosine hydroxylase (TH), in the midbrains of-knockout (KO) mice is responsible for-deficiency-mediated depressive symptoms. We also found that Rev-Erbα, atranscriptional repressor and circadian regulator, is up-regulated in the-KO mouse midbrains and-knockdown Neuro-2a cells. Moreover, brain and muscle Arnt-like protein 1 (BMAL1), thetranscriptional regulator, is also increased in the-KO mouse midbrains and-knockdown cells. Our results further revealed that AHI1 decreases BMAL1/Rev-Erbα expression by interacting with and repressing RAR-related orphan receptor alpha (RORα), a nuclear receptor and transcriptional regulator of circadian genes. Of note,deficiency reversed the reduction in TH expression induced bydeficiency. Moreover, microinfusion of the Rev-Erbα inhibitor SR8278 into the ventral midbrain of-KO mice significantly increased TH expression in the ventral tegmental area and improved their depressive symptoms. These findings provide a mechanistic explanation for a link between AHI1-related behaviors and the circadian clock pathway, indicating an involvement of circadian regulatory proteins in AHI1-regulated mood and behavior.