Clozapine Reverses Dysfunction of Glutamatergic Neurons Derived From Clozapine-Responsive ...

@article{2213735,
   author = {Hříbková, Hana and Svoboda, Ondrej and Bartečků, Elis and Zelinková, Jana and Hořínková, Jana and Lacinova, Lubica and Piskáček, Martin and Lipový, Břetislav and Provazník, Ivo and Glover, Joel C. and Kašpárek, Tomáš and Sun, YuhandMan},
   article_location = {Lausanne, Switzerland},
   article_number = {February 2022},
   doi = {http://dx.doi.org/10.3389/fncel.2022.830757},
   keywords = {schizophrenia; clozapine; hiPSC; glutamate; neuron},
   language = {eng},
   issn = {1662-5102},
   journal = {Frontiers in Cellular Neuroscience},
   title = {Clozapine Reverses Dysfunction of Glutamatergic Neurons Derived From Clozapine-Responsive Schizophrenia Patients},
   url = {https://www.frontiersin.org/articles/10.3389/fncel.2022.830757/full},
   volume = {16},
   year = {2022}
}

TY  - JOUR
ID  - 2213735
AU  - Hříbková, Hana - Svoboda, Ondrej - Bartečků, Elis - Zelinková, Jana - Hořínková, Jana - Lacinova, Lubica - Piskáček, Martin - Lipový, Břetislav - Provazník, Ivo - Glover, Joel C. - Kašpárek, Tomáš - Sun, Yuh-Man
PY  - 2022
TI  - Clozapine Reverses Dysfunction of Glutamatergic Neurons Derived From Clozapine-Responsive Schizophrenia Patients
JF  - Frontiers in Cellular Neuroscience
VL  - 16
IS  - February 2022
SP  - 1-16
EP  - 1-16
PB  - Frontiers
SN  - 16625102
KW  - schizophrenia
KW  - clozapine
KW  - hiPSC
KW  - glutamate
KW  - neuron
UR  - https://www.frontiersin.org/articles/10.3389/fncel.2022.830757/full
N2  - 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.
ER  - 

HŘÍBKOVÁ, Hana, Ondrej SVOBODA, Elis BARTEČKŮ, Jana ZELINKOVÁ, Jana HOŘÍNKOVÁ, Lubica LACINOVA, Martin PISKÁČEK, Břetislav LIPOVÝ, Ivo PROVAZNÍK, Joel C. GLOVER, Tomáš KAŠPÁREK a Yuh-Man SUN. Clozapine Reverses Dysfunction of Glutamatergic Neurons Derived From Clozapine-Responsive Schizophrenia Patients. \textit{Frontiers in Cellular Neuroscience}. Lausanne, Switzerland: Frontiers, 2022, roč.~16, February 2022, s.~1-16. ISSN~1662-5102. Dostupné z: https://dx.doi.org/10.3389/fncel.2022.830757.