Project Summary/Abstract
Seizures, a reflection of extreme excitatory-inhibitory imbalance, are a common neurologic comorbidity in
individuals with intellectual and developmental disabilities (IDDs) and are even more prevalent in syndromic
IDDs. Individuals with Angelman syndrome (AS), a severe neurodevelopmental disorder, are particularly
impacted, as over 90% of AS individuals experience seizures, in addition to other symptoms such as severe
intellectual disability, motor deficits, lack of speech, and sleep disruption. The recurrent seizures affecting AS
individuals are usually difficult to treat and sometimes deadly, yet clinical efforts to alleviate seizure burden have
been stymied by a lack of insight into ictogenic and epileptogenic mechanisms. I hypothesize that improved
understanding of the circuitry underlying seizures in AS model mice can be leveraged toward the development
of improved anti-epileptic therapies to address this unmet clinical need. This project builds upon previous work
from our laboratory demonstrating enhanced epileptogenesis in AS model mice that have undergone seizure
kindling, a process whereby repeated seizure inductions alter neural circuitry to increase seizure susceptibility.
Prominent neuropathology arises post-kindling in AS mice in the dentate gyrus of the hippocampus, making this
region a key mechanistic candidate. Moreover, we have found that deletion of Ube3a, the causative gene in AS,
from GABAergic neurons expressing parvalbumin (PV), but not somatostatin or vasoactive intestinal peptide,
drives seizure phenotypes. In the proposed project, I aim to elucidate the role of PV+ neurons in the seizure
susceptibility of AS model mice. Accordingly, in Aim 1, I will perform whole-cell slice electrophysiology to
determine how the intrinsic firing properties of PV+ neurons in the dentate gyrus differ between AS and wild-type
mice, and whether these properties favor hyperexcitability in AS model mice following seizure kindling. In Aim 2,
I will selectively reinstate Ube3a in PV+ cells to assess whether this confers resilience to kindling and prevents
hippocampal histopathology. These experiments will provide important information at the cellular and circuit
levels regarding how loss of Ube3a promotes seizure, potentially inspiring new treatments for AS and other
epilepsy disorders. In addition to providing novel insights into circuit mechanisms of hyperexcitability, this project
will provide the applicant with excellent training in slice electrophysiology (Philpot and Manis), confocal
microscopy and image analysis (Itano), and the care of pediatric epilepsy patients (Yang), that will prepare him
well for a career as a physician-scientist.