Date of Award

12-2019

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Developmental and Brain Sciences

First Advisor

Susan Zup

Second Advisor

Jin Ho Park

Third Advisor

Vivian Ciaramitaro

Abstract

Serotonin signaling during the perinatal period profoundly impacts brain organization and development, regulating fundamental and long-lasting outcomes such as neuronal excitability and cell death. Sex differences during development have been reported in both serotonin levels and receptor type (excitatory vs. inhibitory) expression in a manner that may leave the male brain more vulnerable to over-excitation. Sexually dimorphic serotonin data fits with a growing body of literature suggesting that male neurons are prone to an excitatory/inhibitory imbalance leaving them ‘easily excitable’. This may help explain the male bias in developmental disorders arising from excitatory/inhibitory imbalance, such as Autism Spectrum Disorder (ASD) and epilepsy. This dissertation explores the influence of sexually dimorphic serotonin system development on sex differences in neuronal excitability in animal models of ASD and epilepsy. While serotonin has been implicated in mediating both ASD pathophysiology and seizure behavior, limited work explores the intersection of serotonin system development and neuronal excitability through a sex-specific lens. We utilized the developmental hyperserotonemia (DHS) rodent model of ASD and found that adult DHS males, but not females, have fewer oxytocin expressing cells in the paraventricular nucleus of the hypothalamus compared to vehicle controls, and that this male-specific oxytocin cell loss may be due to sex differences in serotonin receptor regulation in response to DHS. Additionally, we explored the potentially sexually dimorphic effects of general serotonin receptor agonist 5-methoxytryptamine (5-MT) pretreatment on N-methyl-D-aspartate (NMDA)-induced seizure behavior and hippocampal neuronal loss in developing male and female rats. We report a baseline sex difference in NMDA-induced seizure behavior and neuronal loss, with males exhibiting more severe seizure behavior and neuronal loss compared to females. 5-MT pretreatment abolishes baseline sex differences, providing an anti-convulsant effect for males only. These sex differences appear to be at least partly organized by testosterone, as females given neonatal androgen exhibit a seizure behavior profile in between that of males and females. Overall, our findings suggest that sexually dimorphic serotonin system regulation during development does indeed impact neuronal excitability and thus highlights the need for the inclusion of both sexes in future ASD and seizure research.

Comments

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