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Pathogenic disruption of DISC1-serine racemase binding elicits schizophrenia-like behavior via D-serine depletion

Perturbation of Disrupted-In-Schizophrenia-1 (DISC1) and D-serine/NMDA receptor hypofunction have both been implicated in the pathophysiology of schizophrenia and other psychiatric disorders. In the present study, we demonstrate that these two pathways intersect with behavioral consequences. DISC1 b...

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Autores principales: Ma, T.M., Abazyan, S., Abazyan, B., Nomura, J., Yang, C., Seshadri, S., Sawa, A., Snyder, S.H., Pletnikov, M.V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475769/
https://www.ncbi.nlm.nih.gov/pubmed/22801410
http://dx.doi.org/10.1038/mp.2012.97
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author Ma, T.M.
Abazyan, S.
Abazyan, B.
Nomura, J.
Yang, C.
Seshadri, S.
Sawa, A.
Snyder, S.H.
Pletnikov, M.V.
author_facet Ma, T.M.
Abazyan, S.
Abazyan, B.
Nomura, J.
Yang, C.
Seshadri, S.
Sawa, A.
Snyder, S.H.
Pletnikov, M.V.
author_sort Ma, T.M.
collection PubMed
description Perturbation of Disrupted-In-Schizophrenia-1 (DISC1) and D-serine/NMDA receptor hypofunction have both been implicated in the pathophysiology of schizophrenia and other psychiatric disorders. In the present study, we demonstrate that these two pathways intersect with behavioral consequences. DISC1 binds to and stabilizes serine racemase (SR), the enzyme that generates D-serine, an endogenous co-agonist of the NMDA receptor. Mutant DISC1 fails to bind to SR, facilitating ubiquitination and degradation of SR and a decrease in D-serine production. To elucidate DISC1-SR interactions in vivo, we generated a mouse model of selective and inducible expression of mutant DISC1 in astrocytes, the main source of D-serine in the brain. Expression of mutant DISC1 down-regulates endogenous DISC1 and decreases protein but not mRNA levels of SR, resulting in diminished production of D-serine. In contrast, mutant DISC1 does not alter levels of ALDH1L1, connexins, GLT-1 or binding partners of DISC1 and SR, LIS1 or PICK1. Adult male and female mice with life-long expression of mutant DISC1 exhibit behavioral abnormalities consistent with hypofunction of NMDA neurotransmission. Specifically, mutant mice display greater responses to an NMDA antagonist, MK-801, in open field and pre-pulse inhibition of the acoustic startle tests and are significantly more sensitive to the ameliorative effects of D-serine. These findings support a model wherein mutant DISC1 leads to SR degradation via dominant-negative effects, resulting in D-serine deficiency that diminishes NMDA neurotransmission thus linking DISC1 and NMDA pathophysiologic mechanisms in mental illness.
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spelling pubmed-34757692013-11-01 Pathogenic disruption of DISC1-serine racemase binding elicits schizophrenia-like behavior via D-serine depletion Ma, T.M. Abazyan, S. Abazyan, B. Nomura, J. Yang, C. Seshadri, S. Sawa, A. Snyder, S.H. Pletnikov, M.V. Mol Psychiatry Article Perturbation of Disrupted-In-Schizophrenia-1 (DISC1) and D-serine/NMDA receptor hypofunction have both been implicated in the pathophysiology of schizophrenia and other psychiatric disorders. In the present study, we demonstrate that these two pathways intersect with behavioral consequences. DISC1 binds to and stabilizes serine racemase (SR), the enzyme that generates D-serine, an endogenous co-agonist of the NMDA receptor. Mutant DISC1 fails to bind to SR, facilitating ubiquitination and degradation of SR and a decrease in D-serine production. To elucidate DISC1-SR interactions in vivo, we generated a mouse model of selective and inducible expression of mutant DISC1 in astrocytes, the main source of D-serine in the brain. Expression of mutant DISC1 down-regulates endogenous DISC1 and decreases protein but not mRNA levels of SR, resulting in diminished production of D-serine. In contrast, mutant DISC1 does not alter levels of ALDH1L1, connexins, GLT-1 or binding partners of DISC1 and SR, LIS1 or PICK1. Adult male and female mice with life-long expression of mutant DISC1 exhibit behavioral abnormalities consistent with hypofunction of NMDA neurotransmission. Specifically, mutant mice display greater responses to an NMDA antagonist, MK-801, in open field and pre-pulse inhibition of the acoustic startle tests and are significantly more sensitive to the ameliorative effects of D-serine. These findings support a model wherein mutant DISC1 leads to SR degradation via dominant-negative effects, resulting in D-serine deficiency that diminishes NMDA neurotransmission thus linking DISC1 and NMDA pathophysiologic mechanisms in mental illness. 2012-07-17 2013-05 /pmc/articles/PMC3475769/ /pubmed/22801410 http://dx.doi.org/10.1038/mp.2012.97 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Ma, T.M.
Abazyan, S.
Abazyan, B.
Nomura, J.
Yang, C.
Seshadri, S.
Sawa, A.
Snyder, S.H.
Pletnikov, M.V.
Pathogenic disruption of DISC1-serine racemase binding elicits schizophrenia-like behavior via D-serine depletion
title Pathogenic disruption of DISC1-serine racemase binding elicits schizophrenia-like behavior via D-serine depletion
title_full Pathogenic disruption of DISC1-serine racemase binding elicits schizophrenia-like behavior via D-serine depletion
title_fullStr Pathogenic disruption of DISC1-serine racemase binding elicits schizophrenia-like behavior via D-serine depletion
title_full_unstemmed Pathogenic disruption of DISC1-serine racemase binding elicits schizophrenia-like behavior via D-serine depletion
title_short Pathogenic disruption of DISC1-serine racemase binding elicits schizophrenia-like behavior via D-serine depletion
title_sort pathogenic disruption of disc1-serine racemase binding elicits schizophrenia-like behavior via d-serine depletion
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475769/
https://www.ncbi.nlm.nih.gov/pubmed/22801410
http://dx.doi.org/10.1038/mp.2012.97
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