Neural circuit mechanisms of seizure susceptibility in a mouse model of angelman syndrome

Active Project Grant Awarded Last action

Award ID
F30HD111296
Recipient
Awarding agency
Obligated
$448,496

Award facts

Completion date 96% complete
Place of performance
Chapel Hill, NC 27599, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

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.

Transactions

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Quick answers

Who received award F30HD111296?

F30HD111296 was awarded to University Of North Carolina At Chapel Hill by National Institute of Child Health and Human Development (National Institutes of Health) on July 15, 2024.

How much is award F30HD111296 worth?

$448,496 has been obligated on F30HD111296.

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