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Technology has led to rapid progress in the identification of genes involved in neurodevelopmental disorders such as intellectual disability (ID), but our functional understanding of the causative genes is lagging. Here, we show that the SWI/SNF chromatin remodelling complex is one of the most over-represented cellular components disrupted in ID. We investigated the role of individual subunits of this large protein complex using targeted RNA interference in post-mitotic memory-forming neurons of the Drosophila mushroom body (MB). Knockdown flies were tested for defects in MB morphology, short-term memory and long-term memory. Using this approach, we identified distinct roles for individual subunits of the Drosophila SWI/SNF complex. Bap60, Snr1 and E(y)3 are required for pruning of the MBγ neurons during pupal morphogenesis, while Brm and Osa are required for survival of MBγ axons during ageing. We used the courtship conditioning assay to test the effect of MB-specific SWI/SNF knockdown on short- and long-term memory. Several subunits, including Brm, Bap60, Snr1 and E(y)3, were required in the MB for both short- and long-term memory. In contrast, Osa knockdown only reduced long-term memory. Our results suggest that individual components of the SWI/SNF complex have different roles in the regulation of structural plasticity, survival and functionality of post-mitotic MB neurons. This study highlights the many possible processes that might be disrupted in SWI/SNF-related ID disorders. Our broad phenotypic characterization provides a starting point for understanding SWI/SNF-mediated gene regulatory mechanisms that are important for development and function of post-mitotic neurons., Summary: The SWI/SNF chromatin remodelling complex is the most over-represented protein complex in the intellectual disability. Different components of this complex have distinct roles in development and function of memory-forming neurons in the Drosophila mushroom body.

Technology has led to rapid progress in the identification of genes involved in neurodevelopmental disorders like intellectual disability (ID), but our functional understanding of the causative genes is lagging. Here, we show that the SWI/SNF chromatin remodeling complex is one of the most overrepresented cellular components disrupted in ID. We systematically investigated the role of individual subunits of this large protein complex in post-mitotic memory forming neurons of theDrosophilamushroom body (MB). Using this approach, we have identified novel differential roles for the two prominent conformations of theDrosophilaSWI/SNF complex, known as BAP and PBAP. The PBAP conformation is required post-mitotically for remodeling of the MB γ neurons during morphogenesis and is essential for both short and long-term memory. In contrast, the BAP conformation appears to preferentially effect long-term memory and is associated with γ neuron survival. Our results suggest that different subunits of the SWI/SNF complex may influence learning and memory through diverse and distinct roles in regulating structural plasticity, survival, and functionality of post-mitotic neurons. This study provides novel insight into the neuronal function of individual SWI/SNF subunits and will serve as a basis for understanding SWI/SNF-mediated gene regulatory mechanisms in post-mitotic neurons.