Date on Master's Thesis/Doctoral Dissertation

5-2011

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Anatomical Sciences and Neurobiology

Committee Chair

Casanova, Manuel F.

Author's Keywords

Autism; Cytokines; Immune system; Genetics; Glutathione; Inflammation

Subject

Autism--Genetic aspects; Cytokines

Abstract

Autism Spectrum Disorder (ASD) is an idiopathic pervasive neurodevelopmental disorder associated with various neuropathologies and immunological dysfunctions. Cytokines are regulatory proteins that facilitate communication between the immune and central nervous systems and mediate inflammation, immunity, and hemopoiesis. Previous literature demonstrates that cytokine expression is altered systemically and in the central nervous system of individuals diagnosed with ASD when compared to matched neurotypical controls. Here it is proposed that cytokines are crucial mediators in autism pathogenesis. The central hypothesis of this research posits that an underlying genetic susceptibility in cytokine genes is triggered by environmental exigencies (e.g., stress, infection, ultrasound, hypoxia, pollutant or chemical exposure) during prenatal development. This hypothesis proposes that the convergence of these scenarios during vulnerable periods of neurodevelopment ultimately culminates in the autism phenotype. To test whether cytokines are crucial mediators in autism pathogenesis, the DNA sequences of 22 single nucleotide polymorphisms (SNPs) within 13 cytokine genes were genotyped in a cohort of autistic patients and controls. Three SNP frequencies for both pro-inflammatory [IL1R(+1970)] and anti-inflammatory [IL4(-590) and IL4(-33)] cytokine genes were found to be significantly associated with autism incidence. Next, cytokine mRNA profiles were investigated in post-mortem cortical tissue of eight autistic subjects and eight matched controls. Transcriptional profiling of cytokine genes in five post-mortem cortical regions corresponding to Brodmann Areas 4, 9, 17, 22 and 46 indicated heterogeneous expression of cytokine (TNF-a, IL-6, TGFß-l, IL-1ß) and chemokine (IL-8) transcripts in autistic subjects, but these alterations did not reach statistical significance or reflect values of cortical cytokine translational patterns established in previous literature. Finally, it was shown that systemic cytokine translational expression in the blood plasma of children diagnosed with autism disorder was not modulated with intravenous glutathione administration. These findings indicate that cytokines play an important role in ASD pathogenesis and reveal possible molecular mechanisms that warrant future investigation in etiological research. They also show that the antioxidant agent glutathione, which ostensibly alters cytokine expression at the intracellular level, does not affect systemic cytokine expression or ameliorate behavioral outcome when administered exogenously.

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