Environmental and genetic factors contribute to schizophrenia etiology, yet few studies have demonstrated how environmental stimuli impact genes associated with the disorder. Immediate early genes (IEGs) are of great interest to schizophrenia research because they are activated in response to physiological stress from the environment, and subsequently regulate the expression of downstream genes that are essential to neuropsychiatric function. An IEG, early growth response 3 (EGR3) has been identified as a main gene involved in a network of transcription factors implicated in schizophrenia susceptibility. The serotonin 2A receptor (5-HT2AR) seems to play an important role in schizophrenia and the dysfunction of the 5-HT2AR encoding gene, HTR2A, within the prefrontal cortex (PFC) contributes to multiple psychiatric illnesses including schizophrenia. EGR3's role as a transcription factor that is activated by environmental stimuli suggests it may regulate Htr2a transcription in response to physiological stress, thus affecting 5-HT2AR function in the prefrontal cortex (PFC). The aim of this study was to examine the relationship between Egr3 activation and Htr2a expression after an environmental stimulus. Sleep deprivation is an acute physiological stressor that activates Egr3. Therefore to examine the relationship between Egr3 and Htr2a expression after an acute stress, wild type and Egr3 knockout mice that express EGFP under the control of the Htr2a promoter were sleep deprived for 8 hours. We used immunohistochemistry to determine the location and density of Htr2a-EGFP expression after sleep deprivation and found that Htr2a-EGFP expression was not affected by sex or subregions of the PFC. Additionally, Htr2a-EGFP expression was not affected by the loss of Egr3 or sleep deprivation within the PFC. The LPFC subregions, layers V and VI showed significantly more Htr2a-EGFP expression than layers I-III in all animals for both sleep deprivation and control conditions. Possible explanations for the lack of significant effects in this study may be the limited sample size or possible biological abnormalities in the Htr2a-EGFP mice. Nonetheless, we did successfully visualize the anatomical distribution of Htr2a in the prefrontal cortex via immunohistochemical staining. This study and future studies will provide insight into how Egr3 activation affects Htr2a expression in the PFC and how physiological stress from the environment can alter candidate schizophrenia gene function.
- Stress and Biological Pathways of Schizophrenia: EGR3 Dependent HTR2A Expression in Response to Sleep Deprivation