Assessing Excitation-Transcription Coupling in SCN2A-Related Disorder Mouse Models

Awardee: Jennifer Kearney

Institution: Northwestern University

Grant Amount: $62,492

Funding Period: February 1, 2025 - January 31, 2026

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Summary:

Excitation-transcription coupling is a process that facilitates learning and adaptation to new experiences/stimuli by connecting brain activity to changes in neuronal connections. Altered excitation-transcription coupling has been implicated in other neurodevelopmental disorders and may underlie disrupted sensory processing. SCN2A plays a critical role in backpropagation of action potentials, which is an important electrical signal for excitation-transcription coupling. This raises the possibility that excitation-transcription coupling may be altered in SCN2A-related disorders. Our project will investigate whether excitation-transcription coupling is affected in three SCN2A-related disorder mouse models carrying variants with loss-of-function, gain-of-function or mixed effects on channel function. First, we will examine excitation-transcription capability in isolated neurons. Next, we will evaluate excitation-transcription coupling in mice engaging in behavioral tasks that are dependent on touch. Implicating altered excitation-transcription coupling in SCN2A-related disorders would reveal a downstream point of convergence with other neurodevelopmental disorders and may suggest strategies for interventions focused on shared downstream targets.

Channel scaffolding and its contribution to SCN2A disorders

Awardee: Paul Jenkins

Institution: University of Michigan Medical School

Grant Amount: $61,280.00

Funding Period: February 1, 2024 - January 31, 2025

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Summary:

Thanks to critical genomic data like the Simons Simplex Collection, the scientific community possesses dozens of highly reliable risk genes through the identification of rare de novo variants in patients with autism spectrum disorder (ASD). Loss-of-function in SCN2A, which encodes the neuronal sodium channel NaV1.2, has one of the strongest ASD associations . A large number of SCN2A variants have been shown to alter channel biophysical properties contributing to deficits in electrical signaling within the brain. Strikingly, a significant number of SCN2A variants have little to no detectable effect on channel functional properties, suggesting they are contributing to disease etiology through alternative mechanisms. In this proposal, we will test the hypothesis that these variants contribute to disease phenotypes by disrupting normal channel scaffolding causing channel mislocalization and neuronal dysfunction.

Development of novel gene therapy strategies for treatment of all SCN2A Disorders

Awardee: Samuel Young

Institution: University of Iowa

Grant Amount: $61,068.00

Funding Period: February 1, 2023 - January 31, 2024

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Summary:

SCN2A disorders comprise a complex landscape of both missense and protein-truncating variants, resulting in a diversity of phenotypes that include epilepsy and intellectual disability. Currently, there is no cure for SCN2A Disorders, nor are there methods in development that would provide therapeutic intervention for all forms of SCN2A Disorders. Here, our team proposes proof-of-principle studies that could be beneficial for both missense and protein-truncation cases, providing a single method to treat the entire diversity of SCN2A Disorders.