Publication detail

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

HŘÍBKOVÁ, H. SVOBODA, O. BARTEČKŮ, E. ZELINKOVÁ, J. HOŘÍNKOVÁ, J. LACINOVÁ, Ľ. PISKÁČEK, M. LIPOVÝ, B. PROVAZNÍK, I. GLOVER, J. KAŠPÁREK, T. SUN, Y.

Original Title

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

Type

journal article in Web of Science

Language

English

Original Abstract

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.

Keywords

schizophrenia, clozapine, hiPSC, glutamateneuron

Authors

HŘÍBKOVÁ, H.; SVOBODA, O.; BARTEČKŮ, E.; ZELINKOVÁ, J.; HOŘÍNKOVÁ, J.; LACINOVÁ, Ľ.; PISKÁČEK, M.; LIPOVÝ, B.; PROVAZNÍK, I.; GLOVER, J.; KAŠPÁREK, T.; SUN, Y.

Released

23. 2. 2022

Publisher

Frontiers

Location

Switzerland

ISBN

1662-5102

Periodical

FRONT CELL NEUROSCI

Year of study

16

Number

1

State

Swiss Confederation

Pages from

1

Pages to

16

Pages count

10

URL

https://www.frontiersin.org/articles/10.3389/fncel.2022.830757/full

Full text in the Digital Library

http://hdl.handle.net/11012/203956

BibTex

@article{BUT176788,
  author="Hana {Hříbková} and Ondřej {Svoboda} and Elis {Bartečků} and Jana {Zelinková} and Jana {Hořínková} and Ľubica {Lacinová} and Martin {Piskáček} and Břetislav {Lipový} and Valentine {Provazník} and Joel C. {Glover} and Tomáš {Kašpárek} and Yuh-Man {Sun}",
  title="Clozapine Reverses Dysfunction of Glutamatergic Neurons Derived From Clozapine-Responsive Schizophrenia Patients",
  journal="FRONT CELL NEUROSCI",
  year="2022",
  volume="16",
  number="1",
  pages="1--16",
  doi="10.3389/fncel.2022.830757",
  issn="1662-5102",
  url="https://www.frontiersin.org/articles/10.3389/fncel.2022.830757/full"
}