Date on Master's Thesis/Doctoral Dissertation

12-2019

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

Song, Zhao-Hui

Committee Co-Chair (if applicable)

Barnes, Gregory

Committee Member

Barnes, Gregory

Committee Member

Hood, Joshua

Committee Member

Hein, David

Committee Member

Freedman, Jonathan

Author's Keywords

cannabinoid; neuropharmacology; G protein-coupled receptors; inverse agonist; acyl dopamines

Abstract

Autism Spectrum Disorder (ASD) is a highly heterogenous neurodevelopmental disorder currently estimated by the CDC to affect 1 in 36 children in the U.S.. This uniquely human condition is characterized by a spectrum of symptoms that feature social communication deficits and repetitive behaviors with restricted interest. Autistic individuals commonly exhibit multiple comorbidities, including attention deficit hyperactivity disorder, anxiety, and seizures, which can complicate an already multi-faceted presentation. The majority of ASD cases are idiopathic in nature. Developing a well-validated animal model of ASD for translational research comes with many challenges, but is crucial for advancing our understanding of autism and developing therapeutic interventions. In this dissertation, the BTBR mouse model of idiopathic autism was chosen, due to its strong behavioral and immunological face validity. A pharmacological intervention for the treatment of core autistic symptoms has yet to be identified. While cannabidiol (CBD), the major nonpsychoactive constituent of Cannabis sativa, is suggested to have multiple therapeutic applications, its effect(s) on vi idiopathic autism remains unclear. We hypothesized that chronic CBD treatment would effectively attenuate the autism-like behaviors observed in BTBR mice. Weanlings were injected daily with either vehicle, 20 mg/kg CBD or 50 mg/kg CBD for two weeks, and subsequently assessed with a battery of behavioral assays. Our data indicate that the therapeutic effects of CBD on specific behaviors of BTBR mice are dose-dependent, with high dose CBD treatment attenuating repetitive self-grooming behavior and hyperlocomotion, and low dose CBD rescuing sociability deficits. Gaining a deeper understanding of the neurobiological and immunological underpinnings of idiopathic ASD is essential to the identification of new diagnostic and therapeutic approaches to autism. We sought to characterize the BTBR immune profile using flow cytometric analysis of blood, peripheral lymphoid tissues, and whole brain samples. Our data demonstrate, for the first time, alterations in the peripheral γδ T cell profile and microglial expression of TREM2, both of which have been implicated in clinical ASD. Collectively, this dissertation highlights CBD’s efficacy as a pharmacological intervention for the treatment of core and co-morbid ASD symptoms and identifies γδ T cells and TREM2 expression as potential immunological biomarkers for ASD diagnosis.

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