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Prenatal Stress and Fluoxetine Exposure on Autism Spectrum Disorder (ASD) Risk

thesis
posted on 2022-08-01, 00:00 authored by Anna L Arzuaga
Autism spectrum disorder (ASD) is characterized by social and communication impairments as well as restricted and repetitive behaviors (RRBs). RRBs can be expressed as stereotyped motor behaviors or reduced behavioral flexibility. The increased prevalence of ASD in recent decades and the heterogeneity of symptom severity may arise from a complex interplay of genetic and prenatal risk factors that alter mechanisms of synaptic plasticity. Prenatal stress exposure may be one risk factor for an ASD phenotype in offspring. Selective serotonin reuptake inhibitor (SSRI) treatment can be effective in alleviating maternal stress, but prenatal SSRI exposure itself may lead to autism-like behaviors in offspring. To date, unknown is how prenatal stress, SSRI exposure, or the combination interacts with genetic factors to affect repetitive behaviors and synaptic plasticity in offspring. This project investigated whether prenatal exposure to restraint stress and/or fluoxetine treatment affects the expression of RRBs and synaptic plasticity in C57BL/6J (B6) male and female offspring. The project further examined the effects of these prenatal experiences in genetic mouse models associated with monogenic and polygenic syndromes of autism: the Fmr1-knockout (KO) mouse and the BTBR mouse. The findings suggest that restraint stress in B6 pregnant dams reduced sucrose preference and weight gain that was reversed by fluoxetine. In adult B6 offspring, prenatal exposure to restraint stress and/or fluoxetine treatment increased repetitive behavior in only males and contributed to sex-specific deficits in spatial learning. Long-term potentiation (LTP) induced by theta-burst stimulation (TBS) of Schaffer-commissural afferents in field CA1 was significantly impacted in B6 female offspring exposed to restraint stress alone or combined with fluoxetine. Extension of the identical prenatal manipulations on Fmr1-KO and BTBR mice led to differentially adverse effects in the litter survival rate for these mouse models. To address this issue, a moderate restraint stress protocol was implemented. In BTBR adult offspring, prenatal restraint stress and/or fluoxetine exposure led to sex-specific impairments on spatial learning while elevating locomotor behavior in females only. Overall, the findings suggest that prenatal stress and fluoxetine treatment exposure differentially affect a spectrum of autism-like behaviors in adult offspring of varying genetic susceptibility to ASD.

History

Advisor

Ragozzino, Michael ELarson, John

Chair

Park, Thomas

Department

Biological Sciences

Degree Grantor

University of Illinois at Chicago

Degree Level

  • Doctoral

Degree name

PhD, Doctor of Philosophy

Committee Member

Richmond, Janet Roitman, Jamie

Submitted date

August 2022

Thesis type

application/pdf

Language

  • en

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