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

Molecular Psychiatry volume 18, pages 557–567 (2013)Cite this article

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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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Acknowledgements

We thank members of the SHS and MVP laboratories for help and critical comments, J Ehmsen, A Mustafa, B Paul, M Pucak and K Ishizuka for technical support, R Xu and H Wall for scientific discussions and H Wolosker for providing the SR antiserum. This work is supported by ARRA MH083728 (to MVP), The Brain and Behavior Research Foundation Independent Investigator Award (to MVP), US Public Health Service Grant MH18501 (to SHS) and Young Investigator Award (to BA), NIMH P50 Conti Center Grant (to MVP), The Cell Science Research Foundation Japan (to JN), NIH grants of P50 MH094268 (to AS), P20 MH084018 (to AS), R01 MH069853 (to AS), R01 MH092443 (to AS), R21 MH085226 (to AS), RC1 MH088753 (to AS); NARSAD grants (to AS), SR/RUSK foundation (to AS), Stanley foundation (to AS), Maryland Stem Cell Research Fund (to AS) and in part by MH084020.

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  1. T M Ma and S Abazyan: These authors contributed equally to this work.

Authors and Affiliations

  1. The Solomon H. Snyder Department of Neuroscience, Baltimore, MD, USA

    T M Ma, A Sawa, S H Snyder & M V Pletnikov

  2. Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Baltimore, MD, USA

    S Abazyan, B Abazyan, J Nomura, C Yang & M V Pletnikov

  3. Division of Molecular Medical Science, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan

    J Nomura

  4. Department of Psychiatry and Behavioral Sciences,

    S Seshadri & A Sawa

  5. Division of Molecular Psychiatry, Baltimore, MD, USA

    S Seshadri & A Sawa

  6. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    A Sawa

  7. Departments of Pharmacology and Psychiatry and Behavioral Sciences, Baltimore, MD, USA

    S H Snyder

  8. Department of Molecular and Comparative Pathobiology, Baltimore, MD, USA

    M V Pletnikov

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Ma, T., Abazyan, S., Abazyan, B. et al. Pathogenic disruption of DISC1-serine racemase binding elicits schizophrenia-like behavior via D-serine depletion. Mol Psychiatry 18, 557–567 (2013). https://doi.org/10.1038/mp.2012.97

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