Response competition between neurons and antineurons in the mushroom bodyHighlights d Mushroom body output neurons respond with excitation to odor on-and offset d On and off responses reflect the convergence of oppositely tuned Kenyon cells (KCs) d Opponent KCs compete by eliciting inhibitory feedback from a common interneuron pool d KCs and interneurons communicate through graded potentials rather than spikes
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.
The precise control of motor movements is of fundamental importance to all behaviors in the animal kingdom. Efficient motor behavior depends on dedicated neuronal circuits – such as those in the cerebellum – that are controlled by extensive genetic programs. Autosomal recessive cerebellar ataxias (ARCAs) provide a valuable entry point into how interactions between genetic programs maintain cerebellar motor circuits. We previously identified a striking enrichment of DNA repair genes in ARCAs. How dysfunction of ARCA-associated DNA repair genes leads to preferential cerebellar dysfunction and impaired motor function is however unknown. The expression of ARCA DNA repair genes is not specific to the cerebellum. Only a limited number of animal models for DNA repair ARCAs exist, and, even for these, the interconnection between DNA repair defects, cerebellar circuit dysfunction, and motor behavior is barely established. We used Drosophila melanogaster to characterize the function of ARCA-associated DNA repair genes in the mushroom body (MB), a structure in the Drosophila central brain that shares structural features with the cerebellum. Here, we demonstrate that the MB is required for efficient startle-induced and spontaneous motor behaviors. Inhibition of synaptic transmission and loss-of-function of ARCA-associated DNA repair genes in the MB affected motor behavior in several assays. These motor deficits correlated with increased levels of MB DNA damage, MB Kenyon cell apoptosis and/or alterations in MB morphology. We further show that expression of genes involved in glutamate signaling pathways are highly, specifically, and persistently elevated in the postnatal human cerebellum. Manipulation of glutamate signaling in the MB induced motor defects, Kenyon cell DNA damage and apoptosis. Importantly, pharmacological reduction of glutamate signaling in the ARCA DNA repair models rescued the identified motor deficits, suggesting a role for aberrant glutamate signaling in ARCA-DNA repair disorders. In conclusion, our data highlight the importance of ARCA-associated DNA repair genes and glutamate signaling pathways to the cerebellum, the Drosophila MB and motor behavior. We propose that glutamate signaling may confer preferential cerebellar vulnerability in ARCA-associated DNA repair disorders. Targeting glutamate signaling could provide an exciting therapeutic entry point in this large group of so far untreatable disorders.
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