ArticleMolecular psychiatry2013
Pathogenic disruption of DISC1-serine racemase binding elicits schizophrenia-like behavior via D-serine depletion.
Article in Molecular psychiatry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers, 2 of them syntheses that pooled it.
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Who cites it
89 citing papers in PubMed, 2 syntheses or guidelines pooled it, 148 citations in OpenAlex.
- Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics.Biomolecules · 2022Pooled it
- The impact of Disrupted-in-Schizophrenia 1 (DISC1) on the dopaminergic system: a systematic review.Translational psychiatry · 2017Pooled it
- mtDNA leakage promotes neuron-glia crosstalk to induce epilepsy by cGAS-STING-driven neuroinflammation and serine metabolic reprogramming.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Schizophrenia Pathophysiology: Neurotransmitter Dysfunctions and Biomarker Frontiers.Current topics in medicinal chemistry · 2026Review
- Impact of D-Amino Acids in Schizophrenia.Biomolecules · 2025Review
- The Role of Astrocytes in the Molecular Pathophysiology of Schizophrenia: Between Neurodevelopment and Neurodegeneration.Biomolecules · 2025Review
- Age- and Sex-Specific Regulation of Serine Racemase in the Retina of an Alzheimer's Disease Mouse.Investigative ophthalmology & visual science · 2025Article
- Brain stars take the lead during critical periods of early postnatal brain development: relevance of astrocytes in health and mental disorders.Molecular psychiatry · 2024Review
- In and out: Benchmarking in vitro, in vivo, ex vivo, and xenografting approaches for an integrative brain disease modeling pipeline.Stem cell reports · 2024Review
- Information-Rich, Dual-FunctionJournal of the American Chemical Society · 2023Article
- N-methyl-D-aspartate receptor hypofunction as a potential contributor to the progression and manifestation of many neurological disorders.Frontiers in molecular neuroscience · 2023Review
- Pathology and Astrocytes in Autism.Neuropsychiatric disease and treatment · 2023Review
- Review
- Human Serine Racemase Weakly Binds the Third PDZ Domain of PSD-95.International journal of molecular sciences · 2022Article
- Tyrosine 121 moves revealing a ligandable pocket that couples catalysis to ATP-binding in serine racemase.Communications biology · 2022Article
- d-Amino Acids and pLG72 in Alzheimer's Disease and Schizophrenia.International journal of molecular sciences · 2021Review
- NMDARs, Coincidence Detectors of Astrocytic and Neuronal Activities.International journal of molecular sciences · 2021Review
- The Role of Astrocytes in the Neurorepair Process.Frontiers in cell and developmental biology · 2021Article
- Astrocyte Bioenergetics and Major Psychiatric Disorders.Advances in neurobiology · 2021Review
- Ubiquitination status does not affect Vps34 degradation.Genes & diseases · 2020Article
29 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 4 institutions in 2 countries.
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Abstract
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 downregulates 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 lifelong 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 pathophysiological mechanisms in mental illness.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.