Rebalancing the motor circuit restores movement in a Caenorhabditis elegans model for TDP-43 toxicity

Amyotrophic lateral sclerosis can be caused by abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm of neurons. Here, we use a C. elegans model for TDP-43-induced toxicity to identify the biological mechanisms that lead to disease-related phenotypes. By applying deep behavioral phenotyping and subsequent dissection of the neuromuscular circuit, we show that TDP-43 worms have profound defects in GABA neurons. Moreover, acetylcholine neurons appear functionally silenced. Enhancing functional output of repressed acetylcholine neurons at the level of, among others, G-protein-coupled receptors restores neurotransmission, but inefficiently rescues locomotion. Rebalancing the excitatory-to-inhibitory ratio in the neuromuscular system by simultaneous stimulation of the affected GABA- and acetylcholine neurons, however, not only synergizes the effects of boosting individual neurotransmitter systems, but instantaneously improves movement. Our results suggest that interventions accounting for the altered connectome may be more efficient in restoring motor function than those solely focusing on diseased neuron populations. [Display omitted] •Phenomics profile links ACh and GABA synaptic transmission to TDP-43 proteotoxicity•TDP-43 induces a (mal)adapted, disbalanced, and hyperreactive motor circuit•Reactivation of ACh neurons results in hypercontraction and spastic paralysis•Circuit rebalancing, rather than reactivating affected cell types, restores movement Koopman et al. show that the ALS/FTD-associated protein TDP-43 alters neurotransmission in C. elegans and results in a (mal)adapted, disbalanced, and hyperreactive motor circuit. Rebalancing the circuit by combined treatment of excitatory and inhibitory cells, rather than restoring their individual activities, instantly rescues paralysis and restores normal movement.