According to the most recent CDC report, 1 in 68 children are diagnosed with an autism spectrum disorder (ASD). With 30?40% of individuals with ASDs developing epilepsy, epilepsy represents a major source of morbidity and mortality associated with these disorders. The cellular and molecular mechanisms responsible for epilepsy in individuals with ASDs remain largely unknown. We have developed a new method for making human cortical organoids with functional neural networks from induced pluripotent stem cells (iPSC) and generated iPSC from Phelan-McDermid syndrome (PMDS) patients with epilepsy. Loss of SHANK3 is considered to be the main cause of the neurological and psychiatric deficits in PMDS patients. The main goal of this project is to determine whether and how loss of SHANK3 causes the development of overexcitability deficits in human cortical networks using cortical organoids generated from control and SHANK3-deficient iPSCs. The central hypothesis of this project is that reduced SHANK3 expression in cortical excitatory neurons leads to development of increased intrinsic excitability and seizure-like activity in cortical networks. The following Specific Aims will be completed to test this hypothesis: 1) we will determine the identities of neurons with increased intrinsic excitability in SHANK3-deficient cortical organoids and 2) we will determine whether SHANK3-deficient organoids develop elevated electrical activities in neural networks. The proposed research is significant because it is expected to substantially advance understanding of the cellular and molecular deficits associated with epilepsy in patients with neurodevelopmental disorders and to provide a new platform for epilepsy research and drug discovery.

Public Health Relevance

The proposed research is relevant to public health because the discovery of the molecular, cellular, and network deficits implicated in epilepsy and autism will advance our understanding of the etiology and pathophysiology of these disorders and lead to the development of innovative therapies for patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS104963-01A1
Application #
9601548
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Mamounas, Laura
Project Start
2018-05-01
Project End
2020-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Utah
Department
Neurosciences
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112