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

The result's identifiers

  • Result code in IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14110%2F22%3A00126525" target="_blank" >RIV/00216224:14110/22:00126525 - isvavai.cz</a>

  • Alternative codes found

    RIV/00216305:26220/22:PU143667 RIV/65269705:_____/22:00076099

  • Result on the web

    <a href="https://www.frontiersin.org/articles/10.3389/fncel.2022.830757/full" target="_blank" >https://www.frontiersin.org/articles/10.3389/fncel.2022.830757/full</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.3389/fncel.2022.830757" target="_blank" >10.3389/fncel.2022.830757</a>

Alternative languages

  • Result language

    angličtina

  • Original language name

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

  • Original language 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.

  • Czech name

  • Czech description

Classification

  • Type

    J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database

  • CEP classification

  • OECD FORD branch

    30103 - Neurosciences (including psychophysiology)

Result continuities

  • Project

    Result was created during the realization of more than one project. More information in the Projects tab.

  • Continuities

    P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>S - Specificky vyzkum na vysokych skolach

Others

  • Publication year

    2022

  • Confidentiality

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Data specific for result type

  • Name of the periodical

    Frontiers in Cellular Neuroscience

  • ISSN

    1662-5102

  • e-ISSN

    1662-5102

  • Volume of the periodical

    16

  • Issue of the periodical within the volume

    February 2022

  • Country of publishing house

    CH - SWITZERLAND

  • Number of pages

    16

  • Pages from-to

    1-16

  • UT code for WoS article

    000766591000001

  • EID of the result in the Scopus database

    2-s2.0-85126266275