Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Neuroscience

First Advisor

Timothy P. Roberts

Abstract

Autism Spectrum Disorder (ASD) is an invasive neurodevelopmental disorder characterized by impaired social/communication functioning and restricted and repetitive behaviors. Prevalence estimates report that 1 in 45 children have been diagnosed with ASD. Investigations into the etiology of ASD have observed many, often apparently disparate, neurobiological alterations. In response “biomarkers” (biologically based markers that correlate to ASD-related behavioral phenotypes) have been proposed to aid with research, diagnoses, stratification and future interventions. Indeed, as a result of their association with behavioral phenotypes, biomarkers are somewhat capable of predicting diagnostic status. In addition, such biomarkers allow for the direct study of analogous constructs across species. Auditory M100 latency delays and electrophysiological gamma-band activity (GAMMA) alterations are exemplar biomarkers for ASD.

While studies have begun to uncover the biological bases of these biomarkers, several unresolved questions prevent their full implementation. While both biomarkers have been repeatedly observed, the developmental trajectories are unresolved. Furthermore, while recent studies have observed correlations in healthy adults between cortical GAMMA and relative GABA levels in several systems, the analogous relationship within the auditory system has not been demonstrated. Additionally, if such a correlation does indeed occur, its relation in ASD remains unresolved.

This work characterizes M100 delays and GAMMA as ASD-related biomarkers through five projects. First, a longitudinal MEG study examined the persistence of electrophysiological biomarker in ASD. Secondly a multimodal study resolved the relationship of GAMMA and GABA concentrations in the auditory system in both typically developing individuals (TD) and ASD. Furthermore, exploiting the translational potential of GAMMA (Murine EEG) the analogous relationship was investigated preclinically. Additionally, a mouse model that demonstrates increased sociability was investigated for electrophysiological alterations as a crucial positive control for the use of GAMMA as a biomarker for decreased sociability in ASD. Lastly, this hypersocial mouse model’s in-vitro electrophysiological functioning was characterized utilizing voltage sensitive dye imaging.

This dissertation demonstrates that electrophysiological activity alterations are persistent biomarkers in ASD, and moreover correlate to neurochemistry in TD. Such coupling is less clearly resolved in ASD. Moreover, such a differential coupling phenomenon is recapitulated preclinically. Lastly, hypersocial mice exhibit commensurate alterations to GAMMA.

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