Graduation Date

Summer 8-14-2015

Document Type

Thesis

Degree Name

Master of Science (MS)

Programs

Biochemistry & Molecular Biology

First Advisor

Dr. Anna Dunaevsky

Abstract

Maternal infection during pregnancy, which leads to maternal immune activation (MIA), is an environmental risk factor for autism spectrum disorders (ASD). MIA can be induced in mice and their offspring exhibit behaviors that model the core symptoms of ASD. One of the core behavioral symptoms in ASD patients is presence of increased repetitive behavior, which is modeled by an increase in marble burying in MIA mice. It has been shown that the deficits seen in MIA mice are associated with the dysregulation of cytokine levels in the developing brain, specifically an increase in pro-inflammatory cytokines. In this thesis, I tested whether a reversal of this inflammatory state in the brains of MIA mice by administration of an anti-inflammatory drug, Ibudilast, can ameliorate the behavioral deficit. The results indicated that MIA mice exhibit increased marble burying which is normalized by prenatal administration of Ibudilast without significant effects on control mice. I also tried to establish an additional paradigm of repetitive behavior in the MIA mice, using the rotarod and found that MIA mice have a trend towards increased stereotyped motor routine as measured by an accelerating rotarod test.

Altered behaviors in MIA mice are thought to be mediated by impaired synaptic connectivity. Our lab recently showed structural and functional alterations in synapses in the MIA offspring. An important component of the synapse are astrocytes, a type of glial cell, that regulate synapse formation and function. Whether astrocytic development and function are impaired in MIA offspring is not known. Because cytokines have been shown to modulate the release of transmitters from astrocytes it is possible that increase in inflammatory state in MIA offspring can affect the signaling in astrocytes. Based on these observations, I hypothesized that astrocytic calcium activity is altered in the brains of MIA offspring and proposed to study the same using in-vivo astrocytic calcium imaging.

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