Synaptic Activity Causes Minute-scale Changes in BAF Complex Composition and Function [CUT&Run]

Genes encoding subunits of the BAF (mammalian SWI/SNF) ATP-dependent chromatin remodeling complex are among the those most enriched for deleterious de novo mutations in intellectual disabilities and autism spectrum disorder, but the causative molecular pathways are not understood. Synaptic activity in neurons is critical for learning and memory and proper neural development. While BAF is required for activity-dependent developmental processes, such as dendritic outgrowth, the immediate molecular consequences of neuronal activity on BAF complexes are unknown. Here we report that neuronal activity induces dramatic remodeling of the subunit composition of BAF complexes within 15 minutes, concurrent with both phosphorylation and dephosphorylation of its subunits. These biochemical effects are a convergent phenomenon downstream of multiple calcium-activated signaling pathways in neurons and fibroblasts and correspond to changes in BAF-dependent chromatin accessibility. Our studies imply that BAF decodes signals at the membrane by altering the combinatorial composition of its subunits. Overall design: CUTANDRUN: to investigate the targets of the BAF complex in neurons, primary cortical neurons from E16.5 embryonic mice were cultured for 7 days in vitro. Neuronal nuclei were harvested for Brg1 and Smarcc2 CUTANDRUN.