Metabolic trajectories in developing human neocortical neurons
The shift from glycolysis to oxidative phosphorylation is a key step in neural differentiation. Yet, the timing of metabolic rewiring in the development from progenitors to neurons remains elusive, especially in human corticogenesis. To bridge this gap, here we adopted a unique cell platform based on neocortex-derived human neuroepithelial stem cells, modeling their physiological transition into functional neurons in a 4-mo longitudinal study and until the acquisition of electrophysiological competence. Using quantitative proteomics, combined with NAD(P)H fluorescence lifetime imaging and metabolomics, we investigated the entire differentiation process and describe how metabolic pathways drive cortical neuron maturation. The prevalent metabolic adaptations were then confirmed in a human neocortical specimen. This study provides a spatiotemporal map of neocortical metabolism during development and offers a framework to investigate human neurometabolic disorders.
Authors
- Fabrizia Carli (ORCID: https://orcid.org/0000-0003-2540-1110)
- Gian Carlo Demontis (ORCID: https://orcid.org/0000-0001-7641-0426)
- Francesco Olimpico (ORCID: https://orcid.org/0009-0003-0392-2983)
- Marco Onorati (ORCID: https://orcid.org/0000-0001-8517-930X)
- Agnese Sgalippa (ORCID: https://orcid.org/0000-0002-6395-3525)
- Francesco Finamore (ORCID: https://orcid.org/0009-0005-7875-662X)
- Amalia Gastaldelli (ORCID: https://orcid.org/0000-0003-2594-1651)
- Elisa Degl’Innocenti (ORCID: https://orcid.org/0000-0002-3819-0116)
- Maria Teresa Dell’Anno (ORCID: https://orcid.org/0000-0003-1825-671X)
- Francesco Cardarelli (ORCID: https://orcid.org/0000-0003-3049-5940)
- Gianmarco Ferri (ORCID: https://orcid.org/0000-0002-4341-8920)
- Liam A. McDonnell (ORCID: https://orcid.org/0000-0003-0595-9491)
- Riccardo Ducoli
- Francesco Greco
- Alessandro Passera
- Alessio Zanelli
Institutions
- University of Pisa (IT)
- Fondazione Pisa (IT)
- National Enterprise for NanoScience and NanoTechnology (IT)
- National Research Council (RO)
- Fondazione Toscana Gabriele Monasterio (IT)
- International Flame Research Foundation (IT)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2026-03-31
- DOI
- https://doi.org/10.1073/pnas.2509980123
- Primary Topic
- Neurogenesis and neuroplasticity mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- European Resuscitation Council
- Ministero dell'Università e della Ricerca
- Human Developmental Biology Resource