Seizures are an extreme outcome of excitatory-inhibitory imbalance and are the most common neurological complication in autism spectrum disorder (ASD). Seizures are even more common in syndromic forms of ASD. For example, almost all (more than 90 percent) of individuals with Angelman syndrome (AS) suffer from debilitating seizures, which are difficult to treat and sometimes deadly. Maternal deletions of 15q11-q13 or specific loss-of-function mutations in UBE3A cause AS. The rational design of improved seizure treatments for AS has been stymied by a lack of mechanistic insight into how the loss of UBE3A enhances seizure susceptibility.
To address these issues, Ben Philpot’s lab seeks to elucidate the relevant circuitry and Ube3a isoform-specific mechanisms linked to enhanced seizure susceptibility in AS model mice. The lab previously demonstrated that loss of Ube3a from GABAergic, but not glutamatergic, neurons lowers the seizure threshold and exacerbates epileptogenesis — the gradual process by which seizures render neural circuits increasingly susceptible to subsequent seizures1,2. To help identify the GABAergic cellular subtypes subserving enhanced seizure susceptibility in AS model mice, the Philpot lab will assess seizure outcomes following conditional manipulation of maternal Ube3a expression in parvalbumin-, somatostatin- or vasoactive intestinal peptide-expressing inhibitory neurons.
Philpot and his team also seek to understand which UBE3A protein isoforms and their interacting proteins confer resilience to seizures. UBE3A is an E3 ubiquitin ligase which targets substrate proteins for proteasomal degradation. Thus, by identifying the UBE3A/substrate relationships that govern seizure susceptibility, the lab hopes to identify disease-modifying targets to treat seizures and epileptogenesis. The lab expects that the mechanistic insights gained through these studies will serve the added purpose of guiding therapeutically oriented investigations of seizures and more mild manifestations of excitatory-inhibitory imbalance across the broader spectrum of autism.