Neuronal excitatory-to-inhibitory balance is altered in cerebral organoid models of genetic neurological diseases
Abstract 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 E200...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-10-01
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| Series: | Molecular Brain |
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| Online Access: | https://doi.org/10.1186/s13041-021-00864-w |
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| author | Simote T. Foliaki Benjamin Schwarz Bradley R. Groveman Ryan O. Walters Natalia C. Ferreira Christina D. Orrù Anna Smith Aleksandar Wood Olivia M. Schmit Phoebe Freitag Jue Yuan Wenquan Zou Catharine M. Bosio James A. Carroll Cathryn L. Haigh |
| author_facet | Simote T. Foliaki Benjamin Schwarz Bradley R. Groveman Ryan O. Walters Natalia C. Ferreira Christina D. Orrù Anna Smith Aleksandar Wood Olivia M. Schmit Phoebe Freitag Jue Yuan Wenquan Zou Catharine M. Bosio James A. Carroll Cathryn L. Haigh |
| author_sort | Simote T. Foliaki |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-16T08:41:07Z |
| format | Article |
| id | doaj.art-6bd0dd66c2cd46cbb517d6bd6b03291d |
| institution | Directory Open Access Journal |
| issn | 1756-6606 |
| language | English |
| last_indexed | 2024-12-16T08:41:07Z |
| publishDate | 2021-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Brain |
| spelling | doaj.art-6bd0dd66c2cd46cbb517d6bd6b03291d2022-12-21T22:37:41ZengBMCMolecular Brain1756-66062021-10-0114112310.1186/s13041-021-00864-wNeuronal excitatory-to-inhibitory balance is altered in cerebral organoid models of genetic neurological diseasesSimote T. Foliaki0Benjamin Schwarz1Bradley R. Groveman2Ryan O. Walters3Natalia C. Ferreira4Christina D. Orrù5Anna Smith6Aleksandar Wood7Olivia M. Schmit8Phoebe Freitag9Jue Yuan10Wenquan Zou11Catharine M. Bosio12James A. Carroll13Cathryn L. Haigh14Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of HealthLaboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of HealthLaboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of HealthLaboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of HealthLaboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of HealthLaboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of HealthLaboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of HealthLaboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of HealthLaboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of HealthLaboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of HealthDepartments of Pathology and Neurology, Case Western Reserve University School of MedicineDepartments of Pathology and Neurology, Case Western Reserve University School of MedicineLaboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of HealthLaboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of HealthLaboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of HealthAbstract 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.https://doi.org/10.1186/s13041-021-00864-wNeurodegenerative diseasesNeuronal network communicationNeural oscillation |
| spellingShingle | Simote T. Foliaki Benjamin Schwarz Bradley R. Groveman Ryan O. Walters Natalia C. Ferreira Christina D. Orrù Anna Smith Aleksandar Wood Olivia M. Schmit Phoebe Freitag Jue Yuan Wenquan Zou Catharine M. Bosio James A. Carroll Cathryn L. Haigh Neuronal excitatory-to-inhibitory balance is altered in cerebral organoid models of genetic neurological diseases Molecular Brain Neurodegenerative diseases Neuronal network communication Neural oscillation |
| 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 | Neurodegenerative diseases Neuronal network communication Neural oscillation |
| url | https://doi.org/10.1186/s13041-021-00864-w |
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