A human model of the neurodevelopmental metabolic shift

Sydney N. Pettit; Ariella T. Kornfeld; Celeste Morales; Mollie K. Meffert

doi:10.64898/2026.10.09.758091

A human model of the neurodevelopmental metabolic shift | ResearchHub

Summary The neurodevelopmental metabolic shift transitions the energy sources and metabolic pathways used by neurons to critically support survival, growth, and the timing of 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 genetic induction of neuronal differentiation by NGN2 expression recapitulates hallmarks of metabolic reprogramming associated with neuronal maturation. 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 imaging 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. Highlights □ Establishes a model of the neurodevelopmental metabolic shift using human i 3 Neurons □ Characterizes metabolic correlates across neuronal differentiation □ Demonstrates strategies to assess cellular metabolism and bioenergetics in hPSCs and neurons □ Provides a uniform system to probe metabolic deficiencies in neurological disorders Motivation Several approaches to investigate human neurodevelopmental metabolic reprogramming have been previously reported, however, prior strategies have largely relied on extrinsic factors to provide neurodevelopmental cues, which can impact the uniformity of differentiation as well as being costly, time-consuming, and often technically challenging. As impairments impacting cellular respiration impede proper neuronal development and metabolic deficiencies have been linked to neurodegenerative, neuropsychiatric, and neurodevelopmental disorders, there is a need for efficient and robust models to investigate these early developmental mechanisms. Here, we report a strategy, incorporating an established neuronal differentiation model using induction of stably integrated Neurogenin-2 (NGN2) for rapid generation of excitatory neurons (i3Neurons), which we demonstrate can synchronously recapitulate changes associated with the neurodevelopmental metabolic shift.

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A human model of the neurodevelopmental metabolic shift

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