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Clozapine Reverses Dysfunction of Glutamatergic Neurons Derived From Clozapine-Responsive Schizophrenia Patients

The cellular pathology of schizophrenia and the potential of antipsychotics to target underlying neuronal dysfunctions are still largely unknown. We employed glutamatergic neurons derived from induced pluripotent stem cells (iPSC) obtained from schizophrenia patients with known histories of response...

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Autores principales: Hribkova, Hana, Svoboda, Ondrej, Bartecku, Elis, Zelinkova, Jana, Horinkova, Jana, Lacinova, Lubica, Piskacek, Martin, Lipovy, Bretislav, Provaznik, Ivo, Glover, Joel C., Kasparek, Tomas, Sun, Yuh-Man
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8904748/
https://www.ncbi.nlm.nih.gov/pubmed/35281293
http://dx.doi.org/10.3389/fncel.2022.830757
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author Hribkova, Hana
Svoboda, Ondrej
Bartecku, Elis
Zelinkova, Jana
Horinkova, Jana
Lacinova, Lubica
Piskacek, Martin
Lipovy, Bretislav
Provaznik, Ivo
Glover, Joel C.
Kasparek, Tomas
Sun, Yuh-Man
author_facet Hribkova, Hana
Svoboda, Ondrej
Bartecku, Elis
Zelinkova, Jana
Horinkova, Jana
Lacinova, Lubica
Piskacek, Martin
Lipovy, Bretislav
Provaznik, Ivo
Glover, Joel C.
Kasparek, Tomas
Sun, Yuh-Man
author_sort Hribkova, Hana
collection PubMed
description The cellular pathology of schizophrenia and the potential of antipsychotics to target underlying neuronal dysfunctions are still largely unknown. We employed glutamatergic neurons derived from induced pluripotent stem cells (iPSC) obtained from schizophrenia patients with known histories of response to clozapine and healthy controls to decipher the mechanisms of action of clozapine, spanning from molecular (transcriptomic profiling) and cellular (electrophysiology) levels to observed clinical effects in living patients. Glutamatergic neurons derived from schizophrenia patients exhibited deficits in intrinsic electrophysiological properties, synaptic function and network activity. Deficits in K(+) and Na(+) currents, network behavior, and glutamatergic synaptic signaling were restored by clozapine treatment, but only in neurons from clozapine-responsive patients. Moreover, neurons from clozapine-responsive patients exhibited a reciprocal dysregulation of gene expression, particularly related to glutamatergic and downstream signaling, which was reversed by clozapine treatment. Only neurons from clozapine responders showed return to normal function and transcriptomic profile. Our results underscore the importance of K(+) and Na(+) channels and glutamatergic synaptic signaling in the pathogenesis of schizophrenia and demonstrate that clozapine might act by normalizing perturbances in this signaling pathway. To our knowledge this is the first study to demonstrate that schizophrenia iPSC-derived neurons exhibit a response phenotype correlated with clinical response to an antipsychotic. This opens a new avenue in the search for an effective treatment agent tailored to the needs of individual patients.
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spelling pubmed-89047482022-03-10 Clozapine Reverses Dysfunction of Glutamatergic Neurons Derived From Clozapine-Responsive Schizophrenia Patients Hribkova, Hana Svoboda, Ondrej Bartecku, Elis Zelinkova, Jana Horinkova, Jana Lacinova, Lubica Piskacek, Martin Lipovy, Bretislav Provaznik, Ivo Glover, Joel C. Kasparek, Tomas Sun, Yuh-Man Front Cell Neurosci Neuroscience The cellular pathology of schizophrenia and the potential of antipsychotics to target underlying neuronal dysfunctions are still largely unknown. We employed glutamatergic neurons derived from induced pluripotent stem cells (iPSC) obtained from schizophrenia patients with known histories of response to clozapine and healthy controls to decipher the mechanisms of action of clozapine, spanning from molecular (transcriptomic profiling) and cellular (electrophysiology) levels to observed clinical effects in living patients. Glutamatergic neurons derived from schizophrenia patients exhibited deficits in intrinsic electrophysiological properties, synaptic function and network activity. Deficits in K(+) and Na(+) currents, network behavior, and glutamatergic synaptic signaling were restored by clozapine treatment, but only in neurons from clozapine-responsive patients. Moreover, neurons from clozapine-responsive patients exhibited a reciprocal dysregulation of gene expression, particularly related to glutamatergic and downstream signaling, which was reversed by clozapine treatment. Only neurons from clozapine responders showed return to normal function and transcriptomic profile. Our results underscore the importance of K(+) and Na(+) channels and glutamatergic synaptic signaling in the pathogenesis of schizophrenia and demonstrate that clozapine might act by normalizing perturbances in this signaling pathway. To our knowledge this is the first study to demonstrate that schizophrenia iPSC-derived neurons exhibit a response phenotype correlated with clinical response to an antipsychotic. This opens a new avenue in the search for an effective treatment agent tailored to the needs of individual patients. Frontiers Media S.A. 2022-02-23 /pmc/articles/PMC8904748/ /pubmed/35281293 http://dx.doi.org/10.3389/fncel.2022.830757 Text en Copyright © 2022 Hribkova, Svoboda, Bartecku, Zelinkova, Horinkova, Lacinova, Piskacek, Lipovy, Provaznik, Glover, Kasparek and Sun. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Hribkova, Hana
Svoboda, Ondrej
Bartecku, Elis
Zelinkova, Jana
Horinkova, Jana
Lacinova, Lubica
Piskacek, Martin
Lipovy, Bretislav
Provaznik, Ivo
Glover, Joel C.
Kasparek, Tomas
Sun, Yuh-Man
Clozapine Reverses Dysfunction of Glutamatergic Neurons Derived From Clozapine-Responsive Schizophrenia Patients
title Clozapine Reverses Dysfunction of Glutamatergic Neurons Derived From Clozapine-Responsive Schizophrenia Patients
title_full Clozapine Reverses Dysfunction of Glutamatergic Neurons Derived From Clozapine-Responsive Schizophrenia Patients
title_fullStr Clozapine Reverses Dysfunction of Glutamatergic Neurons Derived From Clozapine-Responsive Schizophrenia Patients
title_full_unstemmed Clozapine Reverses Dysfunction of Glutamatergic Neurons Derived From Clozapine-Responsive Schizophrenia Patients
title_short Clozapine Reverses Dysfunction of Glutamatergic Neurons Derived From Clozapine-Responsive Schizophrenia Patients
title_sort clozapine reverses dysfunction of glutamatergic neurons derived from clozapine-responsive schizophrenia patients
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8904748/
https://www.ncbi.nlm.nih.gov/pubmed/35281293
http://dx.doi.org/10.3389/fncel.2022.830757
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