Abstract

D-serine is a selective endogenous activator of the NMDAR D-serine/glycine site that is involved in abnormal glutamate transmission in schizophrenia. The enzyme serine racemase (SR) directly converts L- serine to D-serine and is present in astrocytes and neurons. Our pilot studies indicated that Disrupted-In- Schizophrenia-1 (DISC1) binds to SR and regulate D-serine production by astrocytes. We hypothesize that abnormal DISC1-SR interaction will affect D-serine metabolism, leading to abnormal glutamatergic neurotransmission and resultant schizophrenia-relevant behaviors.
Specific Aim 1 will determine the mechanisms of DISC1-SR interaction. We will map binding domains for both proteins and compare binding of SR to DISC1 in astrocytes vs. neurons.
Specific Aim 2 will determine the role of DISC1 in the regulation of D-serine production. We will elucidate how changes in DISC1 affect levels of SR and D-serine metabolism in neurons vs. astrocytes.
Specific Aim 3 will evaluate the role of DISC1-SR interaction in glutamatergic synaptic transmission in the cortex and hippocampus. We will determine whether expression of mutant DISC1 in astrocytes vs. neurons alters different parameters of glutamatergic synaptic transmission.
Specific Aim 4 will identify the effects of SR-DISC1 interaction on schizophrenia-like behaviors. We will probe schizophrenia-related behaviors in transgenic mice and determine whether these phenotypic changes can be rescued with D-serine and/or D-cycloserine. The grant application will uncover the molecular mechanisms whereby DISC1 interacts with SR to regulate D-serine production and influences glutamate neurotransmission and schizophrenia-like behaviors.

Public Health Relevance

The grant application proposes to determine the molecular mechanisms whereby a mutant human gene, Disrupted-In-Schizophrenia 1 (DISC1), associated with schizophrenia and related psychiatric disorders, affects metabolism of D-serine, a critical molecule, involved in glutamate neurotransmission known to be altered in schizophrenia. The proposal will advance our understanding of the pathogenic mechanisms of serious psychiatric diseases and will facilitate use of this new model for pre-clinical therapeutic trials.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH083728-05
Application #
8658725
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Panchision, David M
Project Start
2008-06-30
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Li, Ye; Viscidi, Raphael P; Kannan, Geetha et al. (2018) Chronic Toxoplasma gondii Infection Induces Anti-N-Methyl-d-Aspartate Receptor Autoantibodies and Associated Behavioral Changes and Neuropathology. Infect Immun 86:
Khambadkone, Seva G; Cordner, Zachary A; Dickerson, Faith et al. (2018) Nitrated meat products are associated with mania in humans and altered behavior and brain gene expression in rats. Mol Psychiatry :
Terrillion, Chantelle E; Abazyan, Bagrat; Yang, Zhongxi et al. (2017) DISC1 in Astrocytes Influences Adult Neurogenesis and Hippocampus-Dependent Behaviors in Mice. Neuropsychopharmacology 42:2242-2251
Shevelkin, Alexey V; Terrillion, Chantelle E; Abazyan, Bagrat N et al. (2017) Expression of mutant DISC1 in Purkinje cells increases their spontaneous activity and impairs cognitive and social behaviors in mice. Neurobiol Dis 103:144-153
Shevelkin, Alexey V; Terrillion, Chantelle E; Abazyan, Bagrat N et al. (2017) Corrigendum to ""Expression of mutant DISC1 in Purkinje cells increases their spontaneous activity and impairs cognitive and social behaviors in mice"" [Neurobiol. Dis. 103 (2017) 144-153]. Neurobiol Dis 108:362
Umanah, George K E; Pignatelli, Marco; Yin, Xiling et al. (2017) Thorase variants are associated with defects in glutamatergic neurotransmission that can be rescued by Perampanel. Sci Transl Med 9:
Jin, Yunju; Dougherty, Sarah E; Wood, Kevin et al. (2016) Regrowth of Serotonin Axons in the Adult Mouse Brain Following Injury. Neuron 91:748-762
Xia, Meng; Zhu, Shanshan; Shevelkin, Alexey et al. (2016) DISC1, astrocytes and neuronal maturation: a possible mechanistic link with implications for mental disorders. J Neurochem 138:518-24
Saylor, Deanna; Dickens, Alex M; Sacktor, Ned et al. (2016) HIV-associated neurocognitive disorder--pathogenesis and prospects for treatment. Nat Rev Neurol 12:234-48
Nomura, J; Jaaro-Peled, H; Lewis, E et al. (2016) Role for neonatal D-serine signaling: prevention of physiological and behavioral deficits in adult Pick1 knockout mice. Mol Psychiatry 21:386-93

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