Author ORCID Identifier

0000-0003-4131-9205

Defense Date

2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Physiology and Biophysics

First Advisor

Dr. Javier González-Maeso

Abstract

Schizophrenia is a severe neuropsychiatric disorder that presents with diverse symptoms, some of which remain resistant to treatment. Increased risk of neurodevelopmental disorders such as schizophrenia has been observed following gestational infection in humans, leading to development of maternal immune activation (MIA) animal models. Increased density of the serotonin 5-HT2AR receptor (5-HT2AR), the primary target of hallucinogenic drugs and a key target of atypical antipsychotics, has been observed in postmortem antipsychotic-free prefrontal cortex samples from schizophrenia subjects, a change reflected in frontal cortex of adult MIA offspring. To model MIA, we administered 20 mg/kg i.p. of the viral mimetic poly-(I:C) on E12.5 of murine pregnancy and observed increased 5-HT2AR mRNA in adult MIA offspring frontal cortex. Prepulse inhibition of startle deficits, a phenotype seen within disorders such as schizophrenia, were also seen in MIA offspring. Dendritic spines are essential for appropriate synaptic communication and synaptic plasticity. MIA decreases mature mushroom spine density in mouse frontal cortex in a 5-HT2AR-dependent manner, implicating the receptor in MIA-induced synaptic deficits. Due to evidence that glucocorticoid receptor (GR) signaling and stress affect 5-HT2AR expression in other experimental systems, we investigated GR dysregulation as a potential underlying factor for increased 5-HT2AR expression following MIA. We observed decreased GR immunoreactivity in the nuclear, but not cytoplasmic, compartment of MIA offspring frontal cortex as well as decreased GR enrichment at a binding site on the 5-HT2AR promoter. Postmortem human samples demonstrate dysregulation of GR immunoreactivity in prefrontal cortex of schizophrenia subjects relative to controls as well. Directly manipulating GR signaling by administering the endogenous agonist corticosterone increased 5-HT2AR mRNA expression in mouse frontal cortex without affecting 5-HT2CR or dopamine D2 expression. This increase in expression is associated with decreased enrichment of the GR at the 5-HT2AR promoter binding site. Stereotaxic administration of an AAV vector to overexpress a constitutively translocating GR construct, ΔGR, decreased 5-HT2AR, but not 5-HT2CR or D2, expression in mouse frontal cortex. Additionally, ΔGR expression in frontal cortex improved PPI in a 5-HT2AR-dependent manner. These findings support a negative regulatory relationship between GR signaling and 5-HT2AR expression in mouse frontal cortex and may carry implications for the pathophysiology underlying 5-HT2AR dysregulation in neuropsychiatric disorders such as schizophrenia.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

8-11-2021

Available for download on Thursday, August 11, 2022

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