Thirty percent of individuals with autism spectrum disorder (ASD) have recurrent spontaneous seizures (SS). The relationship between the etiology of ASD and epilepsy is an active area of study and one that our laboratory is interested in pursuing as evidence points to a shared disturbance in brain inhibitory systems using the neurotransmitter g-aminobutyric acid (GABA). Most patients suffer from temporal lobe epilepsy and although many molecular changes have been ascribed to its etiology, why certain individuals are at high risk and others are spared is unknown. Temporal lobe epilepsy can be modeled in animals through use of chemically induced prolonged seizures, called status epilepticus. After status epilepticus there is a seizure-free latent period, where ongoing molecular changes occur, followed weeks later by SS, a hallmark of epilepsy. Our laboratory has shown that major changes occur in the composition of GABA-A receptors (GABARs) during the latent period that impairs the function of synaptic receptors in the dentate gyrus, a gatekeeper of excitation in the hippocampus. In my thesis research I demonstrate for the first time that specific changes in GABAR expression are also present during the chronic period of SS, suggesting that altered GABAR composition is preserved throughout the disease process. A major molecular feature of ASD, and one that is seen in multiple ASD models, is marked disruption in development of GABAergic interneurons emerging from their birthplace in ganglionic eminence (GE), and the altered expression of GABARs. In my thesis research using RNA-sequencing I identified that GE expresses almost all of the genes coding for GABAR subunits laying the foundation for future studies on the role of GABARs during development. In addition, using sequencing of chromatin immunoprecipitated fragments containing binding sites for Engrailed 2, a major ASD candidate gene, I show that En2 may be a master regulator of multiple genes in the SFARI database; and, using mouse in utero electroporation, we provide the first evidence that En2 may control the fate of neurons emanating from GE at E12.5. Taken together, my thesis research has uncovered two major areas for future investigation into the overlapping fields of epilepsy and ASD.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/14618 |
| Date | 17 February 2016 |
| Creators | Cogswell, Meaghan |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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