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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.
ContributorsSabatino, Alissa Marie (Author) / Gallitano, Amelia (Thesis director) / Hruschka, Daniel (Thesis director) / Maple, Amanda (Committee member) / Barrett, The Honors College (Contributor)
Created2014-05
Description
ABSTRACT
Environmental and genetic factors influence schizophrenia risk. Individuals who have direct family members with schizophrenia have a much higher incidence. Also, acute stress or life crisis may precede the onset of the disease. This study aims to understand the effects of environment on genes related to schizophrenia risk. It investigates the impact of sleep deprivation as an acute environmental stressor on the expression of Htr2a in mice, a gene that codes for the serotonin 2A receptor (5-HT2AR). HTR2A is associated with schizophrenia risk through genetic association studies and expression is decreased in post-mortem studies of patients with the disease. Furthermore, sleep deprivation as a stressor in human trials has been shown to increase the binding capacity of 5-HT2AR. We hypothesize that sleep deprivation will increase the number of cells expressing Htr2a in the mouse anterior prefrontal cortex when compared to controls. Sleep deprived that mice express EGFP under control of the Htr2a promoter displayed anteroposterior gradients of expression across sagittal sections, with concentrations seen most densely within the prefrontal cortex as well as the anterior pretectal nucleus, thalamic nucleus, as well as the cingulate gyrus. Htr2a-EGFP expression was most densely visualized in cortical layer V and VI pyramidal neurons within the lateral prefrontal cortex of coronal sections. Furthermore, the medial prefrontal cortex contained significantly cells expressing Htr2a¬-EGFP than the lateral prefrontal cortex. Ultimately, the hypothesis was not supported and sleep deprivation did not result in more ¬Htr2a-EGFP expressing cells compared to basal levels. However, expressing cells appeared visibly brighter in sleep-deprived animals when compared to controls, indicating that the amount of intracellular Htr2a-GFP expression may be higher. This study provides strong visual representations of expression gradients following sleep deprivation as an acute stressor and paves the way for future studies regarding 5H-T2AR’s role in schizophrenia.
Environmental and genetic factors influence schizophrenia risk. Individuals who have direct family members with schizophrenia have a much higher incidence. Also, acute stress or life crisis may precede the onset of the disease. This study aims to understand the effects of environment on genes related to schizophrenia risk. It investigates the impact of sleep deprivation as an acute environmental stressor on the expression of Htr2a in mice, a gene that codes for the serotonin 2A receptor (5-HT2AR). HTR2A is associated with schizophrenia risk through genetic association studies and expression is decreased in post-mortem studies of patients with the disease. Furthermore, sleep deprivation as a stressor in human trials has been shown to increase the binding capacity of 5-HT2AR. We hypothesize that sleep deprivation will increase the number of cells expressing Htr2a in the mouse anterior prefrontal cortex when compared to controls. Sleep deprived that mice express EGFP under control of the Htr2a promoter displayed anteroposterior gradients of expression across sagittal sections, with concentrations seen most densely within the prefrontal cortex as well as the anterior pretectal nucleus, thalamic nucleus, as well as the cingulate gyrus. Htr2a-EGFP expression was most densely visualized in cortical layer V and VI pyramidal neurons within the lateral prefrontal cortex of coronal sections. Furthermore, the medial prefrontal cortex contained significantly cells expressing Htr2a¬-EGFP than the lateral prefrontal cortex. Ultimately, the hypothesis was not supported and sleep deprivation did not result in more ¬Htr2a-EGFP expressing cells compared to basal levels. However, expressing cells appeared visibly brighter in sleep-deprived animals when compared to controls, indicating that the amount of intracellular Htr2a-GFP expression may be higher. This study provides strong visual representations of expression gradients following sleep deprivation as an acute stressor and paves the way for future studies regarding 5H-T2AR’s role in schizophrenia.
ContributorsSchmitz, Kirk Andrew (Author) / Gallitano, Amelia (Thesis director) / Stout, Valerie (Committee member) / Maple, Amanda (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2015-05