ALS patient-derived motor neuron networks exhibit microscale dysfunction and mesoscale compensation rendering them highly vulnerable to perturbation

Abstract

Amyotrophic lateral sclerosis affects upper and lower motor neurons, causing progressive neuropathology leading to structural and functional alterations of affected neural networks long prior to development of symptoms. Certain genetic mutations, such as expansions in C9orf72, predispose motor neuron populations to pathological dysfunction. However, it is not known how underlying pathological predisposition affects structural and functional dynamics within vulnerable networks. Here, we studied micro-and mesoscale dynamics of ALS patient derived motor neuron networks over time. We show, for the first time, that ALS patient derived motor neurons with endogenous genetic predisposition develop classical ALS cytopathology in the form of cytoplasmic TDP-43 inclusions and self-organise into computationally efficient networks, albeit with functional hallmarks of higher metabolic cost compared to healthy controls. These hallmarks included microscale impairments and mesoscale compensation including increased centralisation of function. Moreover, we show that these networks are highly susceptible to transient perturbation by exhibiting induced hyperactivity.