Sleep deprivation rapidly upregulates serotonin 2A receptor expression via the immediate early gene Egr3

Serotonin 2A receptors (5-HT 2A Rs) mediate the effects of hallucinogenic drugs and antipsychotic medications, and are reduced in schizophrenia patients’ brains. However, the mechanisms that regulate 5-HT 2A R expression remain poorly understood. We show that an environmental stimulus, sleep deprivation, upregulates 5-HT 2A Rs in the mouse frontal cortex (FC) in just 6-8 hours. This induction requires the immediate early gene transcription factor early growth response 3 ( Egr3 ). Further, EGR3 binds to the Htr2a promoter in the FC in vivo , and drives reporter construct expression in vitro via two Htr2a promoter binding sites. These findings suggest that EGR3 directly regulates FC Htr2a expression in response to physiologic stimuli, providing a mechanism by which environment rapidly alters levels of a brain receptor that mediates symptoms, and treatment, of mental illness. One Sentence Summary Just 6-8 hours of sleep deprivation upregulates brain levels of the receptor that mediates the response to hallucinogens.