Date of Award
2026
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Pharmacology and Experimental Therapeutics
First Advisor
Monsheel Sodhi
Second Advisor
Gonzalo Torres
Abstract
Prenatal stress is a significant risk factor for serious mental illness, including disorders that exhibit substantial social and cognitive deficits. These deficits are often the most debilitating symptoms that patients with serious mental illness face. Unfortunately, the field lacks safe and efficacious treatments for these symptoms. This project demonstrated that prenatally stressed mice exhibit significant cognitive impairments and social deficits, and that these changes are correlated with alterations in the glutamate system. Reduced GluA2 RNA editing is seen in psychiatric disorders that include cognitive and social deficits, in mice with social deficits, and in rats exposed to psychoactive drugs that decrease cognition and sociability. Studies show that increased AMPA receptor firing improves learning and memory but also increases the risk of triggering seizures. We propose increasing GluA2 RNA editing as a potentially safer manipulation of the glutamate system, and that increasing editing at this site would be associated with improved cognition, sociability, and stress resilience. We hypothesized that this would be due to reduced GluA2 expression at the synapse, leading to a predicted increase in the more active GluA2-lacking receptors and driving an increase in long-term potentiation. We hypothesized this would lead to increases in dendritic spine density and maturation. We are the first to evaluate the causal effect of increased GluA2 RNA editing at this site on in vivo synaptic expression of GluA2, dendritic spine morphology, behavior, and stress resilience using two mutant mice that mimic 100% editing and 0% editing. We analyzed these mutants along with wild-type littermates, and behavioral measures were analyzed in nonstressed and stressed mice. At this time, we can report that increasing RNA editing significantly increases dendritic spine maturation, but we have yet to see a robust effect on cognition or sociability, before or after prenatal stress. This may be due to a polymorphism in the GRIA2 gene that we have identified, which is significantly associated with behavior. Finally, we have uncovered several sex differences. We found that females have a higher percentage of mature dendritic spines, specifically stubby spines. We also observed several behavioral differences in response to prenatal stress.
Recommended Citation
Buck, Tristram, "The Role of Glutamate Receptors, RNA Editing, and Prenatal Stress in Cognition, Sociability, and Stress Resilience" (2026). Dissertations. 4326.
https://ecommons.luc.edu/luc_diss/4326
