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Neuronal excitatory-to-inhibitory balance is altered in cerebral organoid models of genetic neurological diseases

The neuro-physiological properties of individuals with genetic pre-disposition to neurological disorders are largely unknown. Here we aimed to explore these properties using cerebral organoids (COs) derived from fibroblasts of individuals with confirmed genetic mutations including PRNP(E200K), triso...

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Autores principales: Foliaki, Simote T., Schwarz, Benjamin, Groveman, Bradley R., Walters, Ryan O., Ferreira, Natalia C., Orrù, Christina D., Smith, Anna, Wood, Aleksandar, Schmit, Olivia M., Freitag, Phoebe, Yuan, Jue, Zou, Wenquan, Bosio, Catharine M., Carroll, James A., Haigh, Cathryn L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507222/
https://www.ncbi.nlm.nih.gov/pubmed/34635127
http://dx.doi.org/10.1186/s13041-021-00864-w
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author Foliaki, Simote T.
Schwarz, Benjamin
Groveman, Bradley R.
Walters, Ryan O.
Ferreira, Natalia C.
Orrù, Christina D.
Smith, Anna
Wood, Aleksandar
Schmit, Olivia M.
Freitag, Phoebe
Yuan, Jue
Zou, Wenquan
Bosio, Catharine M.
Carroll, James A.
Haigh, Cathryn L.
author_facet Foliaki, Simote T.
Schwarz, Benjamin
Groveman, Bradley R.
Walters, Ryan O.
Ferreira, Natalia C.
Orrù, Christina D.
Smith, Anna
Wood, Aleksandar
Schmit, Olivia M.
Freitag, Phoebe
Yuan, Jue
Zou, Wenquan
Bosio, Catharine M.
Carroll, James A.
Haigh, Cathryn L.
author_sort Foliaki, Simote T.
collection PubMed
description The neuro-physiological properties of individuals with genetic pre-disposition to neurological disorders are largely unknown. Here we aimed to explore these properties using cerebral organoids (COs) derived from fibroblasts of individuals with confirmed genetic mutations including PRNP(E200K), trisomy 21 (T21), and LRRK2(G2019S), which are associated with Creutzfeldt Jakob disease, Down Syndrome, and Parkinson’s disease. We utilized no known disease/healthy COs (HC) as normal function controls. At 3–4 and 6–10 months post-differentiation, COs with mutations showed no evidence of disease-related pathology. Electrophysiology assessment showed that all COs exhibited mature neuronal firing at 6–10 months old. At this age, we observed significant changes in the electrophysiology of the COs with disease-associated mutations (dCOs) as compared with the HC, including reduced neuronal network communication, slowing neuronal oscillations, and increased coupling of delta and theta phases to the amplitudes of gamma oscillations. Such changes were linked with the detection of hypersynchronous events like spike-and-wave discharges. These dysfunctions were associated with altered production and release of neurotransmitters, compromised activity of excitatory ionotropic receptors including receptors of kainate, AMPA, and NMDA, and changed levels and function of excitatory glutamatergic synapses and inhibitory GABAergic synapses. Neuronal properties that modulate GABAergic inhibition including the activity of Na–K-Cl cotransport 1 (NKCC1) in Cl(−) homeostasis and the levels of synaptic and extra-synaptic localization of GABA receptors (GABARs) were altered in the T21 COs only. The neurosteroid allopregnanolone, a positive modulator of GABARs, was downregulated in all the dCOs. Treatment with this neurosteroid significantly improved the neuronal communication in the dCOs, possibly through improving the GABAergic inhibition. Overall, without the manifestation of any disease-related pathology, the genetic mutations PRNP(E200K), T21, and LRRK2(G2019S) significantly altered the neuronal network communication in dCOs by disrupting the excitatory-to-inhibitory balance. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13041-021-00864-w.
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spelling pubmed-85072222021-10-20 Neuronal excitatory-to-inhibitory balance is altered in cerebral organoid models of genetic neurological diseases Foliaki, Simote T. Schwarz, Benjamin Groveman, Bradley R. Walters, Ryan O. Ferreira, Natalia C. Orrù, Christina D. Smith, Anna Wood, Aleksandar Schmit, Olivia M. Freitag, Phoebe Yuan, Jue Zou, Wenquan Bosio, Catharine M. Carroll, James A. Haigh, Cathryn L. Mol Brain Research The neuro-physiological properties of individuals with genetic pre-disposition to neurological disorders are largely unknown. Here we aimed to explore these properties using cerebral organoids (COs) derived from fibroblasts of individuals with confirmed genetic mutations including PRNP(E200K), trisomy 21 (T21), and LRRK2(G2019S), which are associated with Creutzfeldt Jakob disease, Down Syndrome, and Parkinson’s disease. We utilized no known disease/healthy COs (HC) as normal function controls. At 3–4 and 6–10 months post-differentiation, COs with mutations showed no evidence of disease-related pathology. Electrophysiology assessment showed that all COs exhibited mature neuronal firing at 6–10 months old. At this age, we observed significant changes in the electrophysiology of the COs with disease-associated mutations (dCOs) as compared with the HC, including reduced neuronal network communication, slowing neuronal oscillations, and increased coupling of delta and theta phases to the amplitudes of gamma oscillations. Such changes were linked with the detection of hypersynchronous events like spike-and-wave discharges. These dysfunctions were associated with altered production and release of neurotransmitters, compromised activity of excitatory ionotropic receptors including receptors of kainate, AMPA, and NMDA, and changed levels and function of excitatory glutamatergic synapses and inhibitory GABAergic synapses. Neuronal properties that modulate GABAergic inhibition including the activity of Na–K-Cl cotransport 1 (NKCC1) in Cl(−) homeostasis and the levels of synaptic and extra-synaptic localization of GABA receptors (GABARs) were altered in the T21 COs only. The neurosteroid allopregnanolone, a positive modulator of GABARs, was downregulated in all the dCOs. Treatment with this neurosteroid significantly improved the neuronal communication in the dCOs, possibly through improving the GABAergic inhibition. Overall, without the manifestation of any disease-related pathology, the genetic mutations PRNP(E200K), T21, and LRRK2(G2019S) significantly altered the neuronal network communication in dCOs by disrupting the excitatory-to-inhibitory balance. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13041-021-00864-w. BioMed Central 2021-10-11 /pmc/articles/PMC8507222/ /pubmed/34635127 http://dx.doi.org/10.1186/s13041-021-00864-w Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Foliaki, Simote T.
Schwarz, Benjamin
Groveman, Bradley R.
Walters, Ryan O.
Ferreira, Natalia C.
Orrù, Christina D.
Smith, Anna
Wood, Aleksandar
Schmit, Olivia M.
Freitag, Phoebe
Yuan, Jue
Zou, Wenquan
Bosio, Catharine M.
Carroll, James A.
Haigh, Cathryn L.
Neuronal excitatory-to-inhibitory balance is altered in cerebral organoid models of genetic neurological diseases
title Neuronal excitatory-to-inhibitory balance is altered in cerebral organoid models of genetic neurological diseases
title_full Neuronal excitatory-to-inhibitory balance is altered in cerebral organoid models of genetic neurological diseases
title_fullStr Neuronal excitatory-to-inhibitory balance is altered in cerebral organoid models of genetic neurological diseases
title_full_unstemmed Neuronal excitatory-to-inhibitory balance is altered in cerebral organoid models of genetic neurological diseases
title_short Neuronal excitatory-to-inhibitory balance is altered in cerebral organoid models of genetic neurological diseases
title_sort neuronal excitatory-to-inhibitory balance is altered in cerebral organoid models of genetic neurological diseases
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507222/
https://www.ncbi.nlm.nih.gov/pubmed/34635127
http://dx.doi.org/10.1186/s13041-021-00864-w
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