The role of the cerebellum in schizophrenia: from cognition to molecular pathways

Detalhes bibliográficos
Autor(a) principal: Yeganeh-Doost, Peyman
Data de Publicação: 2011
Outros Autores: Gruber, Oliver, Falkai, Peter, Schmitt, Andrea
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Clinics
Texto Completo: https://www.revistas.usp.br/clinics/article/view/19414
Resumo: Beside its role in motor coordination, the cerebellum is involved in cognitive function such as attention, working memory, verbal learning, and sensory discrimination. In schizophrenia, a disturbed prefronto-thalamo-cerebellar circuit has been proposed to play a role in the pathophysiology. In addition, a deficit in the glutamatergic N-methyl-D-aspartate (NMDAf) receptor has been hypothesized. The risk gene neuregulin 1 may play a major role in this process. We demonstrated a higher expression of the NMDA receptor subunit 2D in the right cerebellar regions of schizophrenia patients, which may be a secondary upregulation due to a dysfunctional receptor. In contrast, the neuregulin 1 risk variant containing at least one C-allele was associated with decreased expression of NMDA receptor subunit 2C, leading to a dysfunction of the NMDA receptor, which in turn may lead to a dysfunction of the gamma amino butyric acid (GABA) system. Accordingly, from post-mortem studies, there is accumulating evidence that GABAergic signaling is decreased in the cerebellum of schizophrenia patients. As patients in these studies are treated with antipsychotics long term, we evaluated the effect of long-term haloperidol and clozapine treatment in an animal model. We showed that clozapine may be superior to haloperidol in restoring a deficit in NMDA receptor subunit 2C expression in the cerebellum. We discuss the molecular findings in the light of the role of the cerebellum in attention and cognitive deficits in schizophrenia.
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spelling The role of the cerebellum in schizophrenia: from cognition to molecular pathways SchizophreniaCerebellumN-methyl D-aspartate receptorGamma amino butyric acidAntipsychotics Beside its role in motor coordination, the cerebellum is involved in cognitive function such as attention, working memory, verbal learning, and sensory discrimination. In schizophrenia, a disturbed prefronto-thalamo-cerebellar circuit has been proposed to play a role in the pathophysiology. In addition, a deficit in the glutamatergic N-methyl-D-aspartate (NMDAf) receptor has been hypothesized. The risk gene neuregulin 1 may play a major role in this process. We demonstrated a higher expression of the NMDA receptor subunit 2D in the right cerebellar regions of schizophrenia patients, which may be a secondary upregulation due to a dysfunctional receptor. In contrast, the neuregulin 1 risk variant containing at least one C-allele was associated with decreased expression of NMDA receptor subunit 2C, leading to a dysfunction of the NMDA receptor, which in turn may lead to a dysfunction of the gamma amino butyric acid (GABA) system. Accordingly, from post-mortem studies, there is accumulating evidence that GABAergic signaling is decreased in the cerebellum of schizophrenia patients. As patients in these studies are treated with antipsychotics long term, we evaluated the effect of long-term haloperidol and clozapine treatment in an animal model. We showed that clozapine may be superior to haloperidol in restoring a deficit in NMDA receptor subunit 2C expression in the cerebellum. We discuss the molecular findings in the light of the role of the cerebellum in attention and cognitive deficits in schizophrenia. Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo2011-01-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://www.revistas.usp.br/clinics/article/view/1941410.1590/S1807-59322011001300009Clinics; v. 66, suppl. 1 (2011); 71-77 Clinics; v. 66, supl. 1 (2011); 71-77 Clinics; v. 66, suppl. 1 (2011); 71-77 1980-53221807-5932reponame:Clinicsinstname:Universidade de São Paulo (USP)instacron:USPenghttps://www.revistas.usp.br/clinics/article/view/19414/21477Yeganeh-Doost, PeymanGruber, OliverFalkai, PeterSchmitt, Andreainfo:eu-repo/semantics/openAccess2012-05-23T16:39:32Zoai:revistas.usp.br:article/19414Revistahttps://www.revistas.usp.br/clinicsPUBhttps://www.revistas.usp.br/clinics/oai||clinics@hc.fm.usp.br1980-53221807-5932opendoar:2012-05-23T16:39:32Clinics - Universidade de São Paulo (USP)false
dc.title.none.fl_str_mv The role of the cerebellum in schizophrenia: from cognition to molecular pathways
title The role of the cerebellum in schizophrenia: from cognition to molecular pathways
spellingShingle The role of the cerebellum in schizophrenia: from cognition to molecular pathways
Yeganeh-Doost, Peyman
Schizophrenia
Cerebellum
N-methyl D-aspartate receptor
Gamma amino butyric acid
Antipsychotics
title_short The role of the cerebellum in schizophrenia: from cognition to molecular pathways
title_full The role of the cerebellum in schizophrenia: from cognition to molecular pathways
title_fullStr The role of the cerebellum in schizophrenia: from cognition to molecular pathways
title_full_unstemmed The role of the cerebellum in schizophrenia: from cognition to molecular pathways
title_sort The role of the cerebellum in schizophrenia: from cognition to molecular pathways
author Yeganeh-Doost, Peyman
author_facet Yeganeh-Doost, Peyman
Gruber, Oliver
Falkai, Peter
Schmitt, Andrea
author_role author
author2 Gruber, Oliver
Falkai, Peter
Schmitt, Andrea
author2_role author
author
author
dc.contributor.author.fl_str_mv Yeganeh-Doost, Peyman
Gruber, Oliver
Falkai, Peter
Schmitt, Andrea
dc.subject.por.fl_str_mv Schizophrenia
Cerebellum
N-methyl D-aspartate receptor
Gamma amino butyric acid
Antipsychotics
topic Schizophrenia
Cerebellum
N-methyl D-aspartate receptor
Gamma amino butyric acid
Antipsychotics
description Beside its role in motor coordination, the cerebellum is involved in cognitive function such as attention, working memory, verbal learning, and sensory discrimination. In schizophrenia, a disturbed prefronto-thalamo-cerebellar circuit has been proposed to play a role in the pathophysiology. In addition, a deficit in the glutamatergic N-methyl-D-aspartate (NMDAf) receptor has been hypothesized. The risk gene neuregulin 1 may play a major role in this process. We demonstrated a higher expression of the NMDA receptor subunit 2D in the right cerebellar regions of schizophrenia patients, which may be a secondary upregulation due to a dysfunctional receptor. In contrast, the neuregulin 1 risk variant containing at least one C-allele was associated with decreased expression of NMDA receptor subunit 2C, leading to a dysfunction of the NMDA receptor, which in turn may lead to a dysfunction of the gamma amino butyric acid (GABA) system. Accordingly, from post-mortem studies, there is accumulating evidence that GABAergic signaling is decreased in the cerebellum of schizophrenia patients. As patients in these studies are treated with antipsychotics long term, we evaluated the effect of long-term haloperidol and clozapine treatment in an animal model. We showed that clozapine may be superior to haloperidol in restoring a deficit in NMDA receptor subunit 2C expression in the cerebellum. We discuss the molecular findings in the light of the role of the cerebellum in attention and cognitive deficits in schizophrenia.
publishDate 2011
dc.date.none.fl_str_mv 2011-01-01
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv https://www.revistas.usp.br/clinics/article/view/19414
10.1590/S1807-59322011001300009
url https://www.revistas.usp.br/clinics/article/view/19414
identifier_str_mv 10.1590/S1807-59322011001300009
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv https://www.revistas.usp.br/clinics/article/view/19414/21477
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo
publisher.none.fl_str_mv Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo
dc.source.none.fl_str_mv Clinics; v. 66, suppl. 1 (2011); 71-77
Clinics; v. 66, supl. 1 (2011); 71-77
Clinics; v. 66, suppl. 1 (2011); 71-77
1980-5322
1807-5932
reponame:Clinics
instname:Universidade de São Paulo (USP)
instacron:USP
instname_str Universidade de São Paulo (USP)
instacron_str USP
institution USP
reponame_str Clinics
collection Clinics
repository.name.fl_str_mv Clinics - Universidade de São Paulo (USP)
repository.mail.fl_str_mv ||clinics@hc.fm.usp.br
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