Loss of Brg1 promotes seizure development via GABAergic system disruption

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Abstract The Brahma-related gene 1 ( BRG1 ) encodes the catalytic subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex and plays an important role in brain development. Variants in SWI/SNF components are often found in patients with epilepsy, but it is still unclear how loss of BRG1 function contributes to seizure development. In this study, we analyzed the role of Brg1 in seizure susceptibility using zebrafish models with both pharmacological inhibition or genetic reduction of Brg1. Reduced Brg1 function caused seizure-like behavior and increased neuronal activity in larvae, while basic locomotor activity was preserved. Further analyses showed reduced expression of several GABAergic system markers. In contrast, glutamatergic markers did not show major changes. These results point to a selective impairment of inhibitory signaling. When GABA levels were increased pharmacologically, seizure-like behavior was reduced. This suggests that loss of inhibitory transmission plays an important role in the observed hyperexcitability. Unbiased omics analyses also identified changes in proteins associated with vitamin B6 binding. Treatment with active vitamin B6 reduced seizure-like behavior in larvae with reduced Brg1 function. Taken together, these results indicate that Brg1 is required for proper inhibitory neurotransmission and that partial loss of Brg1 function increases seizure susceptibility. These findings may help to better understand why mutations in chromatin remodeling genes are often associated with epilepsy and could support future studies on targeted modulation of inhibitory signaling in these conditions. Significance Statement Chromatin remodeling genes are often mutated in patients with epilepsy, but it is still unclear how these mutations lead to seizures. In this study, we show that reduced function of the chromatin remodeler Brg1 affects inhibitory neurotransmission by impairing the GABAergic system. This leads to increased neuronal activity and seizure-like behavior. Our results identify the chromatin remodeler Brg1 as an important regulator of inhibitory neurotransmission and seizure susceptibility, which may be important for understanding epilepsy associated with neurodevelopmental disorders.

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