Discrimination of motor and sensorimotor effects of phencyclidine and MK-801: Involvement of GluN2C-containing NMDA receptors in psychosis-like models

Non-competitive NMDA receptor (NMDA-R) antagonists like ketamine, phencyclidine (PCP) and MK-801 are routinely used as pharmacological models of schizophrenia. However, the NMDA-R subtypes, neuronal types (e.g., GABA vs. glutamatergic neurons) and brain regions involved in psychotomimetic actions ar...

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Authors: Tarrés-Gatius, Mireia, López Hill, Ximena, Miquel-Rio, Lluís, Castarlenas, Laura, Fabius, Sara, Santana, Noemí, Vilaró, M. Teresa, Artigas, Francesc, Scorza, María Cecilia, Castañé Forn, Anna
Format: article
Publication Date:2022
Country:España
Institution:UVic-UCC
Repository:RiUVic. Repositori institucional de la UVic-UCC
OAI Identifier:oai:dspace.uvic.cat:10854/180278
Online Access:http://hdl.handle.net/10854/180278
https://doi.org/10.1016/j.neuropharm.2022.109079
Access Level:Open access
Keyword:Cervell
Cerebel
Esquizofrènia
Tàlem
61
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oai_identifier_str oai:dspace.uvic.cat:10854/180278
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repository_id_str
spelling Discrimination of motor and sensorimotor effects of phencyclidine and MK-801: Involvement of GluN2C-containing NMDA receptors in psychosis-like modelsTarrés-Gatius, MireiaLópez Hill, XimenaMiquel-Rio, LluísCastarlenas, LauraFabius, SaraSantana, NoemíVilaró, M. TeresaArtigas, FrancescScorza, María CeciliaCastañé Forn, AnnaCervellCerebelEsquizofrèniaTàlem61Non-competitive NMDA receptor (NMDA-R) antagonists like ketamine, phencyclidine (PCP) and MK-801 are routinely used as pharmacological models of schizophrenia. However, the NMDA-R subtypes, neuronal types (e.g., GABA vs. glutamatergic neurons) and brain regions involved in psychotomimetic actions are not fully understood. PCP activates thalamo-cortical circuits after NMDA-R blockade in reticular thalamic GABAergic neurons. GluN2C subunits are densely expressed in thalamus and cerebellum. Therefore, we examined their involvement in the behavioral and functional effects elicited by PCP and MK-801 using GluN2C knockout (GluN2CKO) and wild-type mice, under the working hypothesis that psychotomimetic effects should be attenuated in mutant mice. PCP and MK-801 induced a disorganized and meandered hyperlocomotion in both genotypes. Interestingly, stereotyped behaviors like circling/rotation, rearings and ataxia signs were dramatically reduced in GluN2CKO mice, indicating a better motor coordination in absence of GluN2C subunits. In contrast, other motor or sensorimotor (pre-pulse inhibition of the startle response) aspects of the behavioral syndrome remained unaltered by GluN2C deletion. PCP and MK-801 evoked a general pattern of c-fos activation in mouse brain (including thalamo-cortical networks) but not in the cerebellum, where they markedly reduced c-fos expression, with significant genotype differences paralleling those in motor coordination. Finally, resting-state fMRI showed an enhanced cortico-thalamic-cerebellar connectivity in GluN2CKO mice, less affected by MK-801 than controls. Hence, the GluN2C subunit allows the dissection of the behavioral alterations induced by PCP and MK-801, showing that some motor effects (in particular, motor incoordination), but not deficits in sensorimotor gating, likely depend on GluN2C-containing NMDA-R blockade in cerebellar circuits.info:eu-repo/semantics/acceptedVersionPergamon PressUniversitat de Vic - Universitat Central de Catalunya. Facultat de MedicinaInstitut d’Investigacions Biomèdiques de Barcelona (IIBB-CSIC)Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)Universitat de BarcelonaInstituto de Investigaciones Biológicas Clemente EstableCentro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED)Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)2025202520252022info:eu-repo/semantics/article48 p.application/pdfhttp://hdl.handle.net/10854/180278https://doi.org/10.1016/j.neuropharm.2022.109079reponame:RiUVic. Repositori institucional de la UVic-UCCinstname:UVic-UCCInglésAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:dspace.uvic.cat:10854/1802782026-06-07T19:15:21Z
dc.title.none.fl_str_mv Discrimination of motor and sensorimotor effects of phencyclidine and MK-801: Involvement of GluN2C-containing NMDA receptors in psychosis-like models
title Discrimination of motor and sensorimotor effects of phencyclidine and MK-801: Involvement of GluN2C-containing NMDA receptors in psychosis-like models
spellingShingle Discrimination of motor and sensorimotor effects of phencyclidine and MK-801: Involvement of GluN2C-containing NMDA receptors in psychosis-like models
Tarrés-Gatius, Mireia
Cervell
Cerebel
Esquizofrènia
Tàlem
61
title_short Discrimination of motor and sensorimotor effects of phencyclidine and MK-801: Involvement of GluN2C-containing NMDA receptors in psychosis-like models
title_full Discrimination of motor and sensorimotor effects of phencyclidine and MK-801: Involvement of GluN2C-containing NMDA receptors in psychosis-like models
title_fullStr Discrimination of motor and sensorimotor effects of phencyclidine and MK-801: Involvement of GluN2C-containing NMDA receptors in psychosis-like models
title_full_unstemmed Discrimination of motor and sensorimotor effects of phencyclidine and MK-801: Involvement of GluN2C-containing NMDA receptors in psychosis-like models
title_sort Discrimination of motor and sensorimotor effects of phencyclidine and MK-801: Involvement of GluN2C-containing NMDA receptors in psychosis-like models
dc.creator.none.fl_str_mv Tarrés-Gatius, Mireia
López Hill, Ximena
Miquel-Rio, Lluís
Castarlenas, Laura
Fabius, Sara
Santana, Noemí
Vilaró, M. Teresa
Artigas, Francesc
Scorza, María Cecilia
Castañé Forn, Anna
author Tarrés-Gatius, Mireia
author_facet Tarrés-Gatius, Mireia
López Hill, Ximena
Miquel-Rio, Lluís
Castarlenas, Laura
Fabius, Sara
Santana, Noemí
Vilaró, M. Teresa
Artigas, Francesc
Scorza, María Cecilia
Castañé Forn, Anna
author_role author
author2 López Hill, Ximena
Miquel-Rio, Lluís
Castarlenas, Laura
Fabius, Sara
Santana, Noemí
Vilaró, M. Teresa
Artigas, Francesc
Scorza, María Cecilia
Castañé Forn, Anna
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universitat de Vic - Universitat Central de Catalunya. Facultat de Medicina
Institut d’Investigacions Biomèdiques de Barcelona (IIBB-CSIC)
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)
Universitat de Barcelona
Instituto de Investigaciones Biológicas Clemente Estable
Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED)
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
dc.subject.none.fl_str_mv Cervell
Cerebel
Esquizofrènia
Tàlem
61
topic Cervell
Cerebel
Esquizofrènia
Tàlem
61
description Non-competitive NMDA receptor (NMDA-R) antagonists like ketamine, phencyclidine (PCP) and MK-801 are routinely used as pharmacological models of schizophrenia. However, the NMDA-R subtypes, neuronal types (e.g., GABA vs. glutamatergic neurons) and brain regions involved in psychotomimetic actions are not fully understood. PCP activates thalamo-cortical circuits after NMDA-R blockade in reticular thalamic GABAergic neurons. GluN2C subunits are densely expressed in thalamus and cerebellum. Therefore, we examined their involvement in the behavioral and functional effects elicited by PCP and MK-801 using GluN2C knockout (GluN2CKO) and wild-type mice, under the working hypothesis that psychotomimetic effects should be attenuated in mutant mice. PCP and MK-801 induced a disorganized and meandered hyperlocomotion in both genotypes. Interestingly, stereotyped behaviors like circling/rotation, rearings and ataxia signs were dramatically reduced in GluN2CKO mice, indicating a better motor coordination in absence of GluN2C subunits. In contrast, other motor or sensorimotor (pre-pulse inhibition of the startle response) aspects of the behavioral syndrome remained unaltered by GluN2C deletion. PCP and MK-801 evoked a general pattern of c-fos activation in mouse brain (including thalamo-cortical networks) but not in the cerebellum, where they markedly reduced c-fos expression, with significant genotype differences paralleling those in motor coordination. Finally, resting-state fMRI showed an enhanced cortico-thalamic-cerebellar connectivity in GluN2CKO mice, less affected by MK-801 than controls. Hence, the GluN2C subunit allows the dissection of the behavioral alterations induced by PCP and MK-801, showing that some motor effects (in particular, motor incoordination), but not deficits in sensorimotor gating, likely depend on GluN2C-containing NMDA-R blockade in cerebellar circuits.
publishDate 2022
dc.date.none.fl_str_mv 2022
2025
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10854/180278
https://doi.org/10.1016/j.neuropharm.2022.109079
url http://hdl.handle.net/10854/180278
https://doi.org/10.1016/j.neuropharm.2022.109079
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 48 p.
application/pdf
dc.publisher.none.fl_str_mv Pergamon Press
publisher.none.fl_str_mv Pergamon Press
dc.source.none.fl_str_mv reponame:RiUVic. Repositori institucional de la UVic-UCC
instname:UVic-UCC
instname_str UVic-UCC
reponame_str RiUVic. Repositori institucional de la UVic-UCC
collection RiUVic. Repositori institucional de la UVic-UCC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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