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

Serotonin 2A receptors (5-HT2ARs) mediate the effects of hallucinogenic drugs and antipsychotic medications, and are reduced in schizophrenia patients brains. However, how 5-HT2AR expression is regulated remains poorly understood. We show that 5-HT2ARs are rapidly upregulated in the mouse frontal cortex (FC) in response to an environmental stimulus, sleep deprivation. 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.