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Acute sleep deprivation upregulates serotonin 2A receptors in the frontal cortex of mice via the immediate early gene Egr3

Abstract

Serotonin 2A receptors (5-HT2ARs) mediate the hallucinogenic effects of psychedelic drugs and are a key target of the leading class of medications used to treat psychotic disorders. These findings suggest that dysfunction of 5-HT2ARs may contribute to the symptoms of schizophrenia, a mental illness characterized by perceptual and cognitive disturbances. Indeed, numerous studies have found that 5-HT2ARs are reduced in the brains of individuals with schizophrenia. However, the mechanisms that regulate 5-HT2AR expression remain poorly understood. Here, we show that a physiologic environmental stimulus, sleep deprivation, significantly upregulates 5-HT2AR levels in the mouse frontal cortex in as little as 6–8 h (for mRNA and protein, respectively). This induction requires the activity-dependent immediate early gene transcription factor early growth response 3 (Egr3) as it does not occur in Egr3 deficient (−/−) mice. Using chromatin immunoprecipitation, we show that EGR3 protein binds to the promoter of Htr2a, the gene that encodes the 5-HT2AR, in the frontal cortex in vivo, and drives expression of in vitro reporter constructs via two EGR3 binding sites in the Htr2a promoter. These results suggest that EGR3 directly regulates Htr2a expression, and 5-HT2AR levels, in the frontal cortex in response to physiologic stimuli. Analysis of publicly available post-mortem gene expression data revealed that both EGR3 and HTR2A mRNA are reduced in the prefrontal cortex of schizophrenia patients compared to controls. Together these findings suggest a mechanism by which environmental stimuli alter levels of a brain receptor that may mediate the symptoms, and treatment, of mental illness.

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Fig. 1: Sleep deprivation upregulates Egr3 in a region-dependent manner in the frontal cortex.
Fig. 2: Sleep deprivation upregulates Htr2a in an Egr3-dependent, and region-specific, manner.
Fig. 3: SD increases 5-HT2AR levels in the PFC of WT mice in an Egr3-dependent manner.
Fig. 4: EGR3 binds to the Htr2a promoter in frontal cortex.
Fig. 5: EGR3 drives gene expression via binding sites in the Htr2a promoter and EGR3 and HTR2A expression is reduced in schizophrenia brains.

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Acknowledgements

We are grateful to L Muppana, and D Elizalde for animal colony maintenance and technical assistance, to A. Aden, A. Barkatullah, M. Charbel, and E. Offenberg for assistance with SD studies, to Javier González-Maeso, PhD and Allan Gulledge PhD for expert advice, and to the laboratory of Stanley Watson, MD, PhD, for providing instruction and reagents for situ hybridization.

Funding

This work was supported by National Institutes of Health R01 MH097803 (ALG) and R21 MH113154-01A1 (ALG).

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XZ: Lead, Writing - original draft, Investigation, Formal analysis, Visualization. ABO: Investigation, Formal analysis, Visualization. KTM: Investigation, Formal analysis, Visualization. JC: Investigation, Resources. AMcB: Investigation, Resources. KKM: Investigation. AMM Project administration. CR Investigation. AM: Investigation. SN Investigation. KLB: Investigation. RK Investigation. AB: Investigation. MNG: Investigation. JRL: Investigation. PK: Formal analysis. CH: Formal analysis. MP: Investigation. AO: Investigation. GMK Supervision. ALG: Conceptualization, Funding acquisition, Supervision, Writing–review & editing.

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Correspondence to Amelia L. Gallitano.

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Zhao, X., Ozols, A.B., Meyers, K.T. et al. Acute sleep deprivation upregulates serotonin 2A receptors in the frontal cortex of mice via the immediate early gene Egr3. Mol Psychiatry 27, 1599–1610 (2022). https://doi.org/10.1038/s41380-021-01390-w

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