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

Simple item page
dc.contributor.authorHříbková, Hanacs
dc.contributor.authorSvoboda, Ondřejcs
dc.contributor.authorBartečků, Eliscs
dc.contributor.authorZelinková, Janacs
dc.contributor.authorHořínková, Janacs
dc.contributor.authorLacinová, Ľubicacs
dc.contributor.authorPiskáček, Martincs
dc.contributor.authorLipový, Břetislavcs
dc.contributor.authorProvazník, Ivocs
dc.contributor.authorGlover, Joel C.cs
dc.contributor.authorKašpárek, Tomášcs
dc.contributor.authorSun, Yuh-Mancs
dc.coverage.issue1cs
dc.coverage.volume16cs
dc.date.accessioned2022-03-14T11:53:29Z
dc.date.available2022-03-14T11:53:29Z
dc.date.issued2022-02-23cs
dc.description.abstractThe 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.en
dc.formattextcs
dc.format.extent1-16cs
dc.format.mimetypeapplication/pdfcs
dc.identifier.citationFRONT CELL NEUROSCI. 2022, vol. 16, issue 1, p. 1-16.en
dc.identifier.doi10.3389/fncel.2022.830757cs
dc.identifier.issn1662-5102cs
dc.identifier.other176788cs
dc.identifier.urihttp://hdl.handle.net/11012/203956
dc.language.isoencs
dc.publisherFrontierscs
dc.relation.ispartofFRONT CELL NEUROSCIcs
dc.relation.urihttps://www.frontiersin.org/articles/10.3389/fncel.2022.830757/fullcs
dc.rightsCreative Commons Attribution 4.0 Internationalcs
dc.rights.accessopenAccesscs
dc.rights.sherpahttp://www.sherpa.ac.uk/romeo/issn/1662-5102/cs
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/cs
dc.subjectschizophreniaen
dc.subjectclozapineen
dc.subjecthiPSCen
dc.subjectglutamateneuronen
dc.titleClozapine Reverses Dysfunction of Glutamatergic Neurons Derived From Clozapine-Responsive Schizophrenia Patientsen
dc.type.driverarticleen
dc.type.statusPeer-revieweden
dc.type.versionpublishedVersionen
sync.item.dbidVAV-176788en
sync.item.dbtypeVAVen
sync.item.insts2022.11.15 12:52:25en
sync.item.modts2022.11.15 12:14:25en
thesis.grantorVysoké učení technické v Brně. Fakulta elektrotechniky a komunikačních technologií. Ústav biomedicínského inženýrstvícs
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
fncel16830757.pdf
Size:
3.49 MB
Format:
Adobe Portable Document Format
Description:
fncel16830757.pdf
Download
Collections
Ústav biomedicínského inženýrství