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

Abstract

Intellectual disability (ID) and autism spectrum disorders (ASD) are frequently co-occurring neurodevelopmental disorders and affect 2-3% of the population. Rapid advances in exome and genome sequencing have increased the number of known implicated genes by threefold, to more than a thousand. The main challenges in the field are now to understand the various pathomechanisms associated with this bewildering number of genetic disorders, to identify new genes and to establish causality of variants in still-undiagnosed cases, and to work towards causal treatment options that so far are available only for a few metabolic conditions. To meet these challenges, the research community needs highly efficient model systems. With an increasing number of relevant assays and rapidly developing novel methodologies, the fruit fly Drosophila melanogaster is ideally positioned to change gear in ID and ASD research. The aim of this Review is to summarize some of the exciting work that already has drawn attention to Drosophila as a model for these disorders. We highlight well-established ID- and ASD-relevant fly phenotypes at the (sub)cellular, brain and behavioral levels, and discuss strategies of how this extraordinarily efficient and versatile model can contribute to ‘next generation’ medical genomics and to a better understanding of these disorders.

Systematic phenomics analysis of autism-associated genes reveals parallel networks underlying reversible impairments in habituation

“…zebrafish have investigated the molecular, circuit, and behavioral phenotypic disruptions that result from mutations in diverse ASDassociated genes. These systems have offered valuable insights into the biological mechanisms underlying this heterogeneous group of disorders (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). However, thousands of additional mutations in these and many other genes have been identified in individuals with ASD, and their roles as causative agents, or their pathogenicity, remain ambiguous.…”

Spontaneous social communication in laboratory mice - placing ultrasonic vocalizations in their behavioral context

“…Such knowledge on the phylogeny and ontogeny of social communication abilities is also clinically important to better understand the causes underlying neuropsychiatric conditions. Indeed, several genes associated with autism have been mutated in animal models and lead to atypical social interactions (e.g., mice: (Crawley, 2012;Ey et al, 2011); rats: (Modi et al, 2018); drosophila: (Coll-Tané et al, 2019); monkeys: (Tu et al, 2019)), suggesting that at least certain social brain circuits are conserved during evolution.…”

The histone demethylase KDM5 is required for synaptic structure and function at theDrosophilaneuromuscular junction

“…We show here that KDM5 regulates the expression of genes that are collectively required for normal growth, morphology and function of the Drosophila larval NMJ. This synapse serves as a model for mammalian central nervous system glutamatergic synapses (Coll-Tane et al, 2019;Koh et al, 2000;Menon et al, 2013), which are altered in a number of inherited forms of cognitive impairment, including Fragile X syndrome, Angelman syndrome, and Rett syndrome (Volk et al, 2015). Specifically, our experiments demonstrate that presynaptic KDM5 promotes proper synaptic bouton number and size at the NMJ.…”