Molecular and Functional Mechanisms Underlying Cortical Activity in CACNA1A Epilepsy

Awardee: Fikri Birey

Institution: Emory University

Grant Amount: $57,450

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

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Summary:

This proposal focuses on studying genetic mutations in the CACNA1A gene, which are known to cause a severe neurodevelopmental condition chiefly characterized by epilepsy and cerebellar ataxia. Our team will implement 3D models of human cortical development, namely forebrain assembloids, derived from induced pluripotent stem cells carrying two types of mutations: loss-of-function (LOF) and gain-of-function (GOF). These models will help to better understand how different brain cell types, specifically glutamatergic (excitatory) and GABAergic (inhibitory) neurons, are impacted by these mutations. The study has three main objectives: first, to identify gene expression changes in neurons affected by the mutations; second, to examine how neuronal functions, such as signaling, are altered; and third, to test the effectiveness of a potential therapy known as antisense oligonucleotides (ASOs) in correcting the effects of GOF mutations. This work addresses critical gaps in our understanding by using human-specific models, offering more relevant insights than animal studies, and potentially leading to new treatments for disorders linked to CACNA1A mutations.