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3.2 PARVALBUMIN INTERNEURON IMPAIRMENT INDUCED BY OXIDATIVE STRESS AS A COMMON PATHOLOGICAL MECHANISM IN ANIMAL MODELS OF SCHIZOPHRENIA

BACKGROUND: Parvalbumin inhibitory interneurons (PVIs) are crucial for maintaining proper excitatory/inhibitory balance and high-frequency neuronal synchronization. Their activity supports critical developmental trajectories, sensory and cognitive processing, and social behavior. Despite heterogenei...

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Autores principales: Cabungcal, Jan Harry, Steullet, Pascal, Coyle, Joseph, Didriksen, Michael, Gill, Kathryn, Grace, Anthony, Takao, Hensch, LaMantia, Anthony, Lindemann, Lothar, Maynard, Thomas, Meyer, Urs, Morishita, Hirofumi, O’Donnell, Patricio, Puhl, Matthew, Cuenod, Michel, Do, Kim Q
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5888617/
http://dx.doi.org/10.1093/schbul/sby014.004
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author Cabungcal, Jan Harry
Steullet, Pascal
Coyle, Joseph
Didriksen, Michael
Gill, Kathryn
Grace, Anthony
Takao, Hensch
LaMantia, Anthony
Lindemann, Lothar
Maynard, Thomas
Meyer, Urs
Morishita, Hirofumi
O’Donnell, Patricio
Puhl, Matthew
Cuenod, Michel
Do, Kim Q
author_facet Cabungcal, Jan Harry
Steullet, Pascal
Coyle, Joseph
Didriksen, Michael
Gill, Kathryn
Grace, Anthony
Takao, Hensch
LaMantia, Anthony
Lindemann, Lothar
Maynard, Thomas
Meyer, Urs
Morishita, Hirofumi
O’Donnell, Patricio
Puhl, Matthew
Cuenod, Michel
Do, Kim Q
author_sort Cabungcal, Jan Harry
collection PubMed
description BACKGROUND: Parvalbumin inhibitory interneurons (PVIs) are crucial for maintaining proper excitatory/inhibitory balance and high-frequency neuronal synchronization. Their activity supports critical developmental trajectories, sensory and cognitive processing, and social behavior. Despite heterogeneity in the etiology across schizophrenia and autism spectrum disorder, PVI circuits are altered in these psychiatric disorders. Identifying mechanism(s) underlying PVI deficits is essential to establish treatments targeting in particular cognition. Based on our previous publications and new data, we propose oxidative stress as a common pathological mechanism leading to PVI impairment in schizophrenia and some forms of autism. METHODS: Using immunohistochemistry technique and confocal imaging analysis, we assessed the relationship between oxidative stress (as revealed by 8-oxo-DG immunolabeling) and PVI and their perineuronal net (PNN) in twelve established animal models relevant to autism (i.e., the fmr1 KO and CNV 15q13.3) and schizophrenia (CNV: 22q11, 15q13.3, 1q21, serine racemase (SR) KO, GRIN2A KO, Gclm KO) with or without additional insult (e.g., environmental: Gclm KO + GBR12909, GRIN2A KO + GBR12909, neonatal ventral hippocampal lesion (NVHL), methylazoxymethanol acetate developmental rodent model (MAM) and poly:IC). RESULTS: When PVI deficits in the anterior cingulate cortex were found in these animal models carrying genetic and/or environmental risks relevant to diverse etiological aspects of these disorders, oxidative stress was always present. Specifically, oxidative stress was negatively correlated with the integrity of PVIs and the extracellular perineuronal net enwrapping these interneurons. Oxidative stress may result from dysregulation of systems typically affected in schizophrenia, including glutamatergic, dopaminergic, immune, and antioxidant signaling. As convergent endpoint, redox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models (e.g., Gclm KO, NVHL rats, GRIN2A KO and SR KO mice). D-serine, an allosteric modulator of brain NMDA receptor also protected PVIs and PNN against oxidative stress in SR KO mice. DISCUSSION: In view of the fact that the established pathophysiological processes dopamine excess, immune dysregulation and NMDA receptor hypofunction could all induce oxidative stress and are potentiated by additional oxidative insults, this mechanism could be central to damage of the highly metabolically active PVIs and the PNN surrounding them. Antioxidant systems are therefore potential therapeutic targets, assuming that redox regulators could be applied early, during environmental impacts, long before the clinical emergence of the disease.
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spelling pubmed-58886172018-04-11 3.2 PARVALBUMIN INTERNEURON IMPAIRMENT INDUCED BY OXIDATIVE STRESS AS A COMMON PATHOLOGICAL MECHANISM IN ANIMAL MODELS OF SCHIZOPHRENIA Cabungcal, Jan Harry Steullet, Pascal Coyle, Joseph Didriksen, Michael Gill, Kathryn Grace, Anthony Takao, Hensch LaMantia, Anthony Lindemann, Lothar Maynard, Thomas Meyer, Urs Morishita, Hirofumi O’Donnell, Patricio Puhl, Matthew Cuenod, Michel Do, Kim Q Schizophr Bull Abstracts BACKGROUND: Parvalbumin inhibitory interneurons (PVIs) are crucial for maintaining proper excitatory/inhibitory balance and high-frequency neuronal synchronization. Their activity supports critical developmental trajectories, sensory and cognitive processing, and social behavior. Despite heterogeneity in the etiology across schizophrenia and autism spectrum disorder, PVI circuits are altered in these psychiatric disorders. Identifying mechanism(s) underlying PVI deficits is essential to establish treatments targeting in particular cognition. Based on our previous publications and new data, we propose oxidative stress as a common pathological mechanism leading to PVI impairment in schizophrenia and some forms of autism. METHODS: Using immunohistochemistry technique and confocal imaging analysis, we assessed the relationship between oxidative stress (as revealed by 8-oxo-DG immunolabeling) and PVI and their perineuronal net (PNN) in twelve established animal models relevant to autism (i.e., the fmr1 KO and CNV 15q13.3) and schizophrenia (CNV: 22q11, 15q13.3, 1q21, serine racemase (SR) KO, GRIN2A KO, Gclm KO) with or without additional insult (e.g., environmental: Gclm KO + GBR12909, GRIN2A KO + GBR12909, neonatal ventral hippocampal lesion (NVHL), methylazoxymethanol acetate developmental rodent model (MAM) and poly:IC). RESULTS: When PVI deficits in the anterior cingulate cortex were found in these animal models carrying genetic and/or environmental risks relevant to diverse etiological aspects of these disorders, oxidative stress was always present. Specifically, oxidative stress was negatively correlated with the integrity of PVIs and the extracellular perineuronal net enwrapping these interneurons. Oxidative stress may result from dysregulation of systems typically affected in schizophrenia, including glutamatergic, dopaminergic, immune, and antioxidant signaling. As convergent endpoint, redox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models (e.g., Gclm KO, NVHL rats, GRIN2A KO and SR KO mice). D-serine, an allosteric modulator of brain NMDA receptor also protected PVIs and PNN against oxidative stress in SR KO mice. DISCUSSION: In view of the fact that the established pathophysiological processes dopamine excess, immune dysregulation and NMDA receptor hypofunction could all induce oxidative stress and are potentiated by additional oxidative insults, this mechanism could be central to damage of the highly metabolically active PVIs and the PNN surrounding them. Antioxidant systems are therefore potential therapeutic targets, assuming that redox regulators could be applied early, during environmental impacts, long before the clinical emergence of the disease. Oxford University Press 2018-04 2018-04-01 /pmc/articles/PMC5888617/ http://dx.doi.org/10.1093/schbul/sby014.004 Text en © Maryland Psychiatric Research Center 2018. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Abstracts
Cabungcal, Jan Harry
Steullet, Pascal
Coyle, Joseph
Didriksen, Michael
Gill, Kathryn
Grace, Anthony
Takao, Hensch
LaMantia, Anthony
Lindemann, Lothar
Maynard, Thomas
Meyer, Urs
Morishita, Hirofumi
O’Donnell, Patricio
Puhl, Matthew
Cuenod, Michel
Do, Kim Q
3.2 PARVALBUMIN INTERNEURON IMPAIRMENT INDUCED BY OXIDATIVE STRESS AS A COMMON PATHOLOGICAL MECHANISM IN ANIMAL MODELS OF SCHIZOPHRENIA
title 3.2 PARVALBUMIN INTERNEURON IMPAIRMENT INDUCED BY OXIDATIVE STRESS AS A COMMON PATHOLOGICAL MECHANISM IN ANIMAL MODELS OF SCHIZOPHRENIA
title_full 3.2 PARVALBUMIN INTERNEURON IMPAIRMENT INDUCED BY OXIDATIVE STRESS AS A COMMON PATHOLOGICAL MECHANISM IN ANIMAL MODELS OF SCHIZOPHRENIA
title_fullStr 3.2 PARVALBUMIN INTERNEURON IMPAIRMENT INDUCED BY OXIDATIVE STRESS AS A COMMON PATHOLOGICAL MECHANISM IN ANIMAL MODELS OF SCHIZOPHRENIA
title_full_unstemmed 3.2 PARVALBUMIN INTERNEURON IMPAIRMENT INDUCED BY OXIDATIVE STRESS AS A COMMON PATHOLOGICAL MECHANISM IN ANIMAL MODELS OF SCHIZOPHRENIA
title_short 3.2 PARVALBUMIN INTERNEURON IMPAIRMENT INDUCED BY OXIDATIVE STRESS AS A COMMON PATHOLOGICAL MECHANISM IN ANIMAL MODELS OF SCHIZOPHRENIA
title_sort 3.2 parvalbumin interneuron impairment induced by oxidative stress as a common pathological mechanism in animal models of schizophrenia
topic Abstracts
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5888617/
http://dx.doi.org/10.1093/schbul/sby014.004
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