| Autor: |
Berdenis van Berlekom A; Department of Psychiatry, University Medical Center Utrecht, Brain Center, Utrecht University, 3584 CG Utrecht, The Netherlands.; Department of Translational Neuroscience, University Medical Center Utrecht, Brain Center, Utrecht University, 3584 CG Utrecht, The Netherlands., Kübler R; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Hoogeboom JW; Department of Translational Neuroscience, University Medical Center Utrecht, Brain Center, Utrecht University, 3584 CG Utrecht, The Netherlands., Vonk D; Department of Translational Neuroscience, University Medical Center Utrecht, Brain Center, Utrecht University, 3584 CG Utrecht, The Netherlands., Sluijs JA; Department of Translational Neuroscience, University Medical Center Utrecht, Brain Center, Utrecht University, 3584 CG Utrecht, The Netherlands., Pasterkamp RJ; Department of Translational Neuroscience, University Medical Center Utrecht, Brain Center, Utrecht University, 3584 CG Utrecht, The Netherlands., Middeldorp J; Department of Translational Neuroscience, University Medical Center Utrecht, Brain Center, Utrecht University, 3584 CG Utrecht, The Netherlands.; Department Neurobiology & Aging, Biomedical Primate Research Centre, 2288 GJ Rijswijk, The Netherlands., Kraneveld AD; Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands., Garssen J; Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands.; Danone Nutricia Research, 3584 CT Utrecht, The Netherlands., Kahn RS; Department of Psychiatry, University Medical Center Utrecht, Brain Center, Utrecht University, 3584 CG Utrecht, The Netherlands.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Mental Illness Research, Education, and Clinical Center (VISN 2 South), James J Peters VA Medical Center, Bronx, NY 10468, USA., Hol EM; Department of Translational Neuroscience, University Medical Center Utrecht, Brain Center, Utrecht University, 3584 CG Utrecht, The Netherlands., de Witte LD; Department of Psychiatry, University Medical Center Utrecht, Brain Center, Utrecht University, 3584 CG Utrecht, The Netherlands.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Mental Illness Research, Education, and Clinical Center (VISN 2 South), James J Peters VA Medical Center, Bronx, NY 10468, USA., Boks MP; Department of Psychiatry, University Medical Center Utrecht, Brain Center, Utrecht University, 3584 CG Utrecht, The Netherlands. |
| Abstrakt: |
Evidence of the impact of nutrition on human brain development is compelling. Previous in vitro and in vivo results show that three specific amino acids, histidine, lysine, and threonine, synergistically inhibit mTOR activity and behavior. Therefore, the prenatal availability of these amino acids could be important for human neurodevelopment. However, methods to study the underlying mechanisms in a human model of neurodevelopment are limited. Here, we pioneer the use of human cerebral organoids to investigate the impact of amino acid supplementation on neurodevelopment. In this study, cerebral organoids were exposed to 10 mM and 50 mM of the amino acids threonine, histidine, and lysine. The impact was determined by measuring mTOR activity using Western blots, general cerebral organoid size, and gene expression by RNA sequencing. Exposure to threonine, histidine, and lysine led to decreased mTOR activity and markedly reduced organoid size, supporting findings in rodent studies. RNA sequencing identified comprehensive changes in gene expression, with enrichment in genes related to specific biological processes (among which are mTOR signaling and immune function) and to specific cell types, including proliferative precursor cells, microglia, and astrocytes. Altogether, cerebral organoids are responsive to nutritional exposure by increasing specific amino acid concentrations and reflect findings from previous rodent studies. Threonine, histidine, and lysine exposure impacts the early development of human cerebral organoids, illustrated by the inhibition of mTOR activity, reduced size, and altered gene expression. |
