A human model of the neurodevelopmental metabolic shift

Abstract

The neurodevelopmental metabolic shift transitions the metabolic pathways used by neurons to generate energy in order to critically support survival, growth, and functional maturation. To better understand metabolic regulation during human neuronal development and to facilitate the study of early neurodevelopmental disorders impacting this time window, establishing a combination of effective human model systems will be required. We report that a streamlined strategy using the genetic induction of neuronal differentiation by NGN2 expression recapitulates hallmarks of metabolic reprogramming associated with neurodevelopment. The approach is refined to increase the uniformity of differentiation, allowing reproducible high-throughput assessments. We validate appropriate readouts of metabolic function, including gene expression, cellular respiration, and mitochondrial morphology, which can be combined to present a cohesive assessment of metabolic status and reliance on oxidative phosphorylation relative to glycolysis. Collectively, the strategy presented will enhance the ability of investigators to gather foundational and disease-related insights into regulatory mechanisms of the metabolic shift critical to successful neuronal differentiation.