Graduation Year


Document Type




Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medical Sciences

Major Professor

Edwin Weeber, Ph.D.

Committee Member

Dominic D’Agostino, Ph.D.

Committee Member

Jay Dean, Ph.D.

Committee Member

Jaya Padmanabhan, Ph.D.


Epilepsy, ganaxolone, ketones, metabolism, GABA


Angelman syndrome (AS) is a rare genetic and neurological disorder presenting with severe developmental delay, ataxia, epilepsy, and lack of speech. AS is associated with a neuron-specific loss of function of the maternal UBE3A allele, a gene encoding an E3 ubiquitin ligase. Currently, no cure exists for this disorder; however, recent research using an AS mouse model suggests that pharmacological intervention is plausible, and can alleviate some of the detrimental phenotypes reported in AS patients.

Although there is no curative treatment for AS, seizure medication and behavioral therapies are most commonly prescribed in order to minimize symptoms. However, these options only moderately improve quality of life and can cause adverse side effects, such as alterations in mood and cognition following seizure treatment. Unfortunately, epilepsy is a common cause of death in AS and affects greater than 80% of AS patients, with 77% of those patients remaining refractory. The severity of seizures and lack of consistently effective anti-epileptic medications for AS patients demonstrates a considerable need for other therapeutic options. The goal of this work was to evaluate the effects of seizure therapies that have proven beneficial for treating refractory epilepsy in seizure-related disorders. These studies focused specifically on advances in both a pharmacological and dietary therapy evaluated in the AS mouse model.

Previous work in our lab has demonstrated the importance of interneurons and GABAergic tone in hippocampal network regulation and cognition. GABA is an important modulator of synaptic plasticity, and learning increases both inhibitory synaptogenesis and GABA release from hippocampal inhibitory neurons. A neuronal excitatory/inhibitory imbalance, coupled with decreased GABAergic tone, altered synaptic plasticity, and impaired cognition have been reported in the AS mouse model. Therefore, we proposed to examine two therapeutic strategies used in seizure treatment – a ketone ester (KE) supplement, which is thought to increase the [GABA]/[glutamate] ratio via alterations in brain metabolism, and ganaxolone, a positive allosteric modulator of GABAA receptors. We evaluated the effects of each therapeutic on learning and cognitive enhancement, alterations in synaptic function, and anticonvulsant activity. We hypothesized that both the KE and ganaxolone would demonstrate anticonvulsant efficacy in both behavioral and chemiconvulsant seizure models. Additionally, as chronic epilepsy has been linked to progressive cognitive and memory impairment which may be related to GABA deficiencies, we hypothesized that both therapeutics would improve cognition and modulate synaptic plasticity (i.e., synaptic function).

KE administration produced sustained ketosis and improved motor coordination, learning and memory, and synaptic plasticity in AS mice. The KE was also anticonvulsant and altered brain amino acid metabolism in AS treated animals. Ganaxolone was anxiolytic, anticonvulsant, and improved motor deficits in AS mice. Four weeks of treatment also led to recovery of spatial working memory and hippocampal synaptic plasticity deficits. This study demonstrates that the KE and ganaxolone ameliorate many of the behavioral abnormalities in the adult AS mouse, possibly through modulations of GABAergic tone. These results support clinical investigation of both the KE and ganaxolone in AS, which may lead to the development of a novel treatment for AS patients.

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