Acute sleep deprivation upregulates serotonin 2A receptors in the frontal cortex of mice via the immediate early gene Egr3
Xiu-Li Zhao, Annika B. Ozols, K. Meyers, J. Campbell, Andrew McBride, Ketan K Marballi, Amanda M. Maple, C. Raskin, A. Mishra, Serena Noss, Kelsey L. Beck, R. Khoshaba, Amulya Bhaskara, Meghna N. Godbole, James R. Lish, P. Kang, Chengcheng Hu, Mikael Palner, Agnete Overgaard, Gitte M. Knudsen, Amelia L. Gallitano
Molecular Psychiatry January 10, 2022 DOI: 10.1038/s41380-021-01390-w (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Basic science laboratory study Peer reviewed |
|---|---|
| Population | Mice (frontal cortex) and publicly available human post-mortem prefrontal cortex gene expression data from schizophrenia patients and controls |
| Intervention | Sleep deprivation |
| Duration | 6-8 hours of sleep deprivation |
| Topics | Serotonin |
| Key points | Sleep deprivation significantly upregulated 5-HT2AR mRNA and protein in mouse frontal cortex within 6-8 hours, an effect absent in Egr3-deficient mice. EGR3 bound the Htr2a promoter and drove its expression, suggesting EGR3 directly regulates Htr2a in response to physiologic stimuli. Publicly available post-mortem data showed reduced EGR3 and HTR2A mRNA in schizophrenia prefrontal cortex versus controls. |
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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cites 12
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- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Pilot Study of Psilocybin Treatment for Anxiety in Patients With Advanced-Stage Cancer Archives of General Psychiatry September 7, 2010
- Serotonin research: contributions to understanding psychoses TIPS - Trends in Pharmacological Sciences August 1, 2008
- Psychedelics as Medicines: An Emerging New Paradigm Clinical Pharmacology & Therapeutics November 4, 2016
and 7 more in the library