Large neutral amino acid levels tune perinatal neuronal excitability and survival.

Cell 2023 Apr 27

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Little is known about the critical metabolic changes that neural cells have to undergo during development and how temporary shifts in this program can influence brain circuitries and behavior. Inspired by the discovery that mutations in SLC7A5, a transporter of metabolically essential large neutral amino acids (LNAAs), lead to autism, we employed metabolomic profiling to study the metabolic states of the cerebral cortex across different developmental stages. We found that the forebrain undergoes significant metabolic remodeling throughout development, with certain groups of metabolites showing stage-specific changes, but what are the consequences of perturbing this metabolic program? By manipulating Slc7a5 expression in neural cells, we found that the metabolism of LNAAs and lipids are interconnected in the cortex. Deletion of Slc7a5 in neurons affects the postnatal metabolic state, leading to a shift in lipid metabolism. Additionally, it causes stage- and cell-type-specific alterations in neuronal activity patterns, resulting in a long-term circuit dysfunction. Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Lisa S Knaus, Bernadette Basilico, Daniel Malzl, Maria Gerykova Bujalkova, Mateja Smogavec, Lena A Schwarz, Sarah Gorkiewicz, Nicole Amberg, Florian M Pauler, Christian Knittl-Frank, Marianna Tassinari, Nuno Maulide, Thomas Rülicke, Jörg Menche, Simon Hippenmeyer, Gaia Novarino. Large neutral amino acid levels tune perinatal neuronal excitability and survival. Cell. 2023 Apr 27;186(9):1950-1967.e25