Spatial and temporal boundaries of NMDA receptor hypofunction leading to schizophrenia

Abstract The N-methyl-d-aspartate receptor hypofunction is one of the most prevalent models of schizophrenia. For example, healthy subjects treated with uncompetitive N-methyl-d-aspartate receptor antagonists elicit positive, negative, and cognitive-like symptoms of schizophrenia. Patients with anti...

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Autores principales:	Kazu Nakazawa, Vivek Jeevakumar, Kazuhito Nakao
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Psychiatry RC435-571
Acceso en línea:	https://doaj.org/article/050326895e8e40fd9406bf979b567391
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spelling	oai:doaj.org-article:050326895e8e40fd9406bf979b5673912021-12-02T15:18:49ZSpatial and temporal boundaries of NMDA receptor hypofunction leading to schizophrenia10.1038/s41537-016-0003-32334-265Xhttps://doaj.org/article/050326895e8e40fd9406bf979b5673912017-02-01T00:00:00Zhttps://doi.org/10.1038/s41537-016-0003-3https://doaj.org/toc/2334-265XAbstract The N-methyl-d-aspartate receptor hypofunction is one of the most prevalent models of schizophrenia. For example, healthy subjects treated with uncompetitive N-methyl-d-aspartate receptor antagonists elicit positive, negative, and cognitive-like symptoms of schizophrenia. Patients with anti-N-methyl-d-aspartate receptor encephalitis, which is likely caused by autoantibody-mediated down-regulation of cell surface N-methyl-d-aspartate receptors, often experience psychiatric symptoms similar to schizophrenia initially. However, where and when N-methyl-d-aspartate receptor hypofunction occurs in the brain of schizophrenic patients is poorly understood. Here we review the findings from N-methyl-d-aspartate receptor antagonist and autoantibody models, postmortem studies on N-methyl-d-aspartate receptor subunits, as well as the global and cell-type-specific knockout mouse models of subunit GluN1. We compare various conditional GluN1 knockout mouse strains, focusing on the onset of N-methyl-d-aspartate receptor deletion and on the cortical cell-types. Based on these results, we hypothesize that N-methyl-d-aspartate receptor hypofunction initially occurs in cortical GABAergic neurons during early postnatal development. The resulting GABA neuron maturation deficit may cause reduction of intrinsic excitability and GABA release, leading to disinhibition of pyramidal neurons. The cortical disinhibition in turn could elicit glutamate spillover and subsequent homeostatic down regulation of N-methyl-d-aspartate receptor function in pyramidal neurons in prodromal stage. These two temporally-distinct N-methyl-d-aspartate receptor hypofunctions may be complimentary, as neither alone may not be able to fully explain the entire schizophrenia pathophysiology. Potential underlying mechanisms for N-methyl-d-aspartate receptor hypofunction in cortical GABA neurons are also discussed, based on studies of naturally-occurring N-methyl-d-aspartate receptor antagonists, neuregulin/ErbB4 signaling pathway, and theoretical analysis of excitatory/inhibitory balance.Kazu NakazawaVivek JeevakumarKazuhito NakaoNature PortfolioarticlePsychiatryRC435-571ENnpj Schizophrenia, Vol 3, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Psychiatry RC435-571
spellingShingle	Psychiatry RC435-571 Kazu Nakazawa Vivek Jeevakumar Kazuhito Nakao Spatial and temporal boundaries of NMDA receptor hypofunction leading to schizophrenia
description	Abstract The N-methyl-d-aspartate receptor hypofunction is one of the most prevalent models of schizophrenia. For example, healthy subjects treated with uncompetitive N-methyl-d-aspartate receptor antagonists elicit positive, negative, and cognitive-like symptoms of schizophrenia. Patients with anti-N-methyl-d-aspartate receptor encephalitis, which is likely caused by autoantibody-mediated down-regulation of cell surface N-methyl-d-aspartate receptors, often experience psychiatric symptoms similar to schizophrenia initially. However, where and when N-methyl-d-aspartate receptor hypofunction occurs in the brain of schizophrenic patients is poorly understood. Here we review the findings from N-methyl-d-aspartate receptor antagonist and autoantibody models, postmortem studies on N-methyl-d-aspartate receptor subunits, as well as the global and cell-type-specific knockout mouse models of subunit GluN1. We compare various conditional GluN1 knockout mouse strains, focusing on the onset of N-methyl-d-aspartate receptor deletion and on the cortical cell-types. Based on these results, we hypothesize that N-methyl-d-aspartate receptor hypofunction initially occurs in cortical GABAergic neurons during early postnatal development. The resulting GABA neuron maturation deficit may cause reduction of intrinsic excitability and GABA release, leading to disinhibition of pyramidal neurons. The cortical disinhibition in turn could elicit glutamate spillover and subsequent homeostatic down regulation of N-methyl-d-aspartate receptor function in pyramidal neurons in prodromal stage. These two temporally-distinct N-methyl-d-aspartate receptor hypofunctions may be complimentary, as neither alone may not be able to fully explain the entire schizophrenia pathophysiology. Potential underlying mechanisms for N-methyl-d-aspartate receptor hypofunction in cortical GABA neurons are also discussed, based on studies of naturally-occurring N-methyl-d-aspartate receptor antagonists, neuregulin/ErbB4 signaling pathway, and theoretical analysis of excitatory/inhibitory balance.
format	article
author	Kazu Nakazawa Vivek Jeevakumar Kazuhito Nakao
author_facet	Kazu Nakazawa Vivek Jeevakumar Kazuhito Nakao
author_sort	Kazu Nakazawa
title	Spatial and temporal boundaries of NMDA receptor hypofunction leading to schizophrenia
title_short	Spatial and temporal boundaries of NMDA receptor hypofunction leading to schizophrenia
title_full	Spatial and temporal boundaries of NMDA receptor hypofunction leading to schizophrenia
title_fullStr	Spatial and temporal boundaries of NMDA receptor hypofunction leading to schizophrenia
title_full_unstemmed	Spatial and temporal boundaries of NMDA receptor hypofunction leading to schizophrenia
title_sort	spatial and temporal boundaries of nmda receptor hypofunction leading to schizophrenia
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/050326895e8e40fd9406bf979b567391
work_keys_str_mv	AT kazunakazawa spatialandtemporalboundariesofnmdareceptorhypofunctionleadingtoschizophrenia AT vivekjeevakumar spatialandtemporalboundariesofnmdareceptorhypofunctionleadingtoschizophrenia AT kazuhitonakao spatialandtemporalboundariesofnmdareceptorhypofunctionleadingtoschizophrenia
_version_	1718387428425728000

Spatial and temporal boundaries of NMDA receptor hypofunction leading to schizophrenia

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