Abstract
BackgroundNeural circuits are initially assembled during development when neurons synapse with potential partners and later refined as appropriate connections stabilize into mature synapses while inappropriate contacts are eliminated. Disruptions to this synaptogenic process impair connectivity optimization and can cause neurodevelopmental disorders. Intellectual disability (ID) and autism spectrum disorder (ASD) are often characterized by synaptic overgrowth, with the maintenance of immature or inappropriate synapses. Such synaptogenic defects can occur through mutation of a single gene, such as fragile X mental retardation protein (FMRP) loss causing the neurodevelopmental disorder fragile X syndrome (FXS). FXS represents the leading heritable cause of ID and ASD, but many other genes that play roles in ID and ASD have yet to be identified.ResultsIn a Drosophila FXS disease model, one dfmr150M null mutant stock exhibits previously unreported axonal overgrowths at developmental and mature stages in the giant fiber (GF) escape circuit. These excess axon projections contain both chemical and electrical synapse markers, indicating mixed synaptic connections. Extensive analyses show these supernumerary synapses connect known GF circuit neurons, rather than new, inappropriate partners, indicating hyperconnectivity within the circuit. Despite the striking similarities to well-characterized FXS synaptic defects, this new GF circuit hyperconnectivity phenotype is driven by genetic background mutations in this dfmr150M stock. Similar GF circuit synaptic overgrowth is not observed in independent dfmr1 null alleles. Bulked segregant analysis (BSA) was combined with whole genome sequencing (WGS) to identify the quantitative trait loci (QTL) linked to neural circuit hyperconnectivity. The results reveal 8 QTL associated with inappropriate synapse formation and maintenance in the dfmr150M mutant background.ConclusionsSynaptogenesis is a complex, precisely orchestrated neurodevelopmental process with a large cohort of gene products coordinating the connectivity, synaptic strength, and excitatory/inhibitory balance between neuronal partners. This work identifies a number of genetic regions that contain mutations disrupting proper synaptogenesis within a particularly well-mapped neural circuit. These QTL regions contain potential new genes involved in synapse formation and refinement. Given the similarity of the synaptic overgrowth phenotype to known ID and ASD inherited conditions, identifying these genes should increase our understanding of these devastating neurodevelopmental disease states.
Highlights
Neural circuits are initially assembled during development when neurons synapse with potential partners and later refined as appropriate connections stabilize into mature synapses while inappropriate contacts are eliminated
Given the similarity of the synaptic overgrowth phenotype to known Intellectual disability (ID) and autism spectrum disorder (ASD) inherited conditions, identifying these genes should increase our understanding of these devastating neurodevelopmental disease states
The primary presynaptic sites of the GF interneuron (GFI) are at the inframedial bridge (IB; Fig. 1a, arrowhead), which synapses with the peripherally synapsing interneuron (PSI) and giant fiber coupled (GFC) neurons 1–4, and the axonal bends (Fig. 1a, arrows), which synapse with the tergotrochanteral motor neuron (TTMn) and GFC2–3 ([29, 30, 38])
Summary
Neural circuits are initially assembled during development when neurons synapse with potential partners and later refined as appropriate connections stabilize into mature synapses while inappropriate contacts are eliminated Disruptions to this synaptogenic process impair connectivity optimization and can cause neurodevelopmental disorders. Results: In a Drosophila FXS disease model, one dfmr150M null mutant stock exhibits previously unreported axonal overgrowths at developmental and mature stages in the giant fiber (GF) escape circuit These excess axon projections contain both chemical and electrical synapse markers, indicating mixed synaptic connections. With the onset of environmental sensory input, this refinement process continues, mediated by multiple activity-dependent synaptic mechanisms [8] Genetic disruption of this precise synapse initiation and maturation program causes neurodevelopmental disorders of intellectual and autistic disabilities [9]. The most common heritable state is fragile X syndrome (FXS), a monogenic disorder and key model for studying links between synaptic connectivity and disease [10]
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