Doctor of Philosophy (PhD)
Pharmacology and Experimental Neuroscience
Autism spectrum disorder (ASD) and intellectual disability (ID) are highly prevalent neurodevelopmental disorders characterized by social and communication deficits, stereotyped behaviors, cognitive dysfunction, and deficits in adaptive behaviors. The pathogenesis underlying these disorders remains unknown, and thus no pharmacologic or genetic therapies are currently available. Recent progress in the field has shown that haploinsufficiency of the AT-rich interactive domain-containing 1B (ARID1B) gene is a genetic cause of ASD and ID. Our lab recently developed an Arid1b knockout mouse model to better study its role in the pathogenesis of these disorders. One theory regarding the cause of neurodevelopmental disorders is disruption of the excitatory/inhibitory balance in the brain. We previously showed that interneuron deficits lead to an excitatory/inhibitory imbalance in Arid1b knockout mice, playing a significant role in the observed behavioral phenotypes. Interneurons are highly heterogenous cell types in the brain; however, little is known regarding how the different subtypes modulate various behaviors. In chapter 2, we dissect the individual roles of the two most populous interneurons in the cerebral cortex, parvalbumin and somatostatin subtypes, in ASD/ID behaviors seen with ARID1B haploinsufficiency. We show that parvalbumin interneurons affect social and emotional behaviors, while somatostatin interneurons primarily affect stereotyped behaviors and cognitive function.
In addition to interneuron deficits, several studies have also implicated altered neurite outgrowth of cortical projection neurons in ASD and ID. Furthermore, deficits in neurotrophic signaling, a master regulator of neurite outgrowth, is also frequently observed. In chapter 3, we examine a potential role of ARID1B in regulating neurite development of excitatory neurons during corticogenesis. We show that loss of the Arid1b gene leads to disrupted neurite outgrowth and altered development of the corpus callosum. Additionally, we suggest a likely role of ARID1B in the BDNF neurotrophic signaling pathway. Together, these studies provide insight into possible roles of ARID1B during neurogenesis, shedding further insight into the pathogenesis of ASD and ID.
Smith, Amanda L., "Roles of autism gene ARID1B in murine brain development and behavior" (2019). Theses & Dissertations. 420.
Available for download on Saturday, December 11, 2021