Humans interact with numerous chemical compounds with direct health implications, with several able to induce developmental neurotoxicity (DNT), which bear developmental, behavioral, and cognitive consequences from a young age. Current guidelines for DNT testing are notably costly, time consuming, and unsuitable for testing large numbers of chemicals. Therefore, there is a need for adequate alternatives to conventional animal testing for neurotoxicity and DNT. Here we show that detailed kinematic analysis can provide a strong indicator for DNT, using known (chlorpyrifos, CPS) or putative (β-N-methylamino-L-alanine, BMAA) neurotoxic compounds. We exposed Drosophila melanogaster to these compounds during development and evaluated for common general toxicity — notably developmental survival and pupal positioning, together with the FlyWalker system, a detailed adult kinematics evaluation method.At concentrations that do not induce general toxicity, the solvent DMSO had a significant effect on kinematic parameters. Nonetheless, CPS not only induced developmental lethality but also significantly impaired coordination in comparison to DMSO, altering 16 motor parameters, validating the usefulness of our kinematic approach.Interestingly, BMAA, although not lethal during development, induced a dose-dependent motor decay, targeting most parameters in young adult animals, phenotypically resembling normally aged, non-exposed flies. This effect was subsequently attenuated during ageing, indicating an adaptive response. Furthermore, BMAA induced an abnormal terminal differentiation of leg motor neurons, without inducing degeneration, underpinning the observed altered mobility phenotype. Overall, our results support our kinematic approach as a novel, highly sensitive and reliable tool to assess potential DNT of chemical compounds.
Wired neurons form new presynaptic boutons in response to increased synaptic activity, but the mechanism by which this occurs remains uncertain. The neuromuscular junction (NMJ) is a synapse formed between motor neurons (MNs) and skeletal muscle fibers and is critical for control of muscle contraction. Because Drosophila MNs have clearly discernible boutons that display robust structural plasticity, it is the ideal system in which to study bouton genesis. Here we show using ex-vivo and by live imaging that in response to depolarization, MNs form new boutons by membrane blebbing, a pressure-driven mechanism used in 3-D migration, but never described as a neuronal remodeling strategy. In accordance, F-actin is decreased during bouton growth (a hallmark of blebs) and we show that non-muscle myosin-II (a master regulator of blebbing) is recruited to newly formed boutons. Furthermore, we discovered that muscle contraction plays a mechanical role in activity-dependent plasticity, promoting bouton addition by increasing MNs confinement. Overall, we provide a novel mechanism by which established circuits create new boutons allowing their structural expansion and plasticity, using trans-synaptic physical forces as the main driving force. Understanding MN-muscle interplay during activity-dependent plasticity can help clarify the mechanisms leading to MN degeneracy observed in neuromuscular diseases.
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