Individual components of the SWI/SNF chromatin remodelling complex have distinct roles in memory neurons of theDrosophilamushroom body

Abstract

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.

Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome

“…Postmitotic MB neurons were targeted using the R14H06-Gal4 driver line, which we have characterised previously 26,27 . R14H06-Gal4 is highly specific for the MB in adult and larval fly brains 46 . It is also expressed in a few cells of the ventral nerve chord, which appear to be chordotonal sensory neurons involved in balance and locomotion.…”

Intellectual disability and autism spectrum disorders ‘on the fly’: insights from Drosophila

“…Recent research into ID/ASD-associated genes highlights the complexity of regulating short- and long-term memory. Unexpectedly, ID genes encoding different subunits of the same protein complex, SWI/SNF, differentially affect MB-encoded short- versus long-term memory (Chubak et al, 2019).…”

The chromatin remodeler ISWI acts during Drosophila development to regulate adult sleep

“…Chromatin dynamics are critical for appropriate gene expression during key developmental time points ( 25 ). At a behavioral level, disruption to individual chromatin remodeling genes has been associated with abnormal sleep and circadian rhythms ( 26 , 27 ), memory ( 28 , 29 ), and social function ( 30 ) in animal models. Thus, dysfunction of these important gene regulatory hubs likely results in a multitude of downstream biological effects, contributing to behavioral pleiotropy seen in NDDs.…”