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

M, T; Abazyan, Sofya; Abazyan, Bagrat; Nomura, Jun; Yang, Chunxia; Seshadri, Saurav; Sawa, Akira; Snyder, Solomon H.; Pletnikov, Mikhail V.

doi:10.1038/mp.2012.97

Cited by 134 publications

(178 citation statements)

References 76 publications

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“…Similar to the DISC1 and neuregulin1 knockout mice, PSD95 homozygous KO's are not lethal, and the heterozygous animals share prepulse inhibition, hyperactivity, and enhanced LTP phenotypes (Desbonnet et al, 2009;Dyck et al, 2009;Kato et al, 2010;Le Greves et al, 2006;Yao et al, 2004). Interestingly, alterations in the localization and function of DISC1 and neuregulin1 are linked to abnormalities of the NMDA receptor signaling complex that includes PSD95 (Balu and Coyle, 2011;Geddes et al, 2011;Ma et al, 2013;Schmitt et al, 2011). The wellcharacterized effects of pharmacologic blockade of NMDA receptors, which yield a schizophreniform phenotype, support the hypothesis that disruption of synaptic plasticity, regardless of the mechanism, contributes to the signs and symptoms of schizophrenia.…”

Section: Data From Post-synaptic Density 95 (Psd95)mentioning

confidence: 99%

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

McCullumsmith

Hammond

Shan

et al. 2013

Neuropsychopharmacol

106

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We propose that postmortem tissue is an underutilized substrate that may be used to translate genetic and/or preclinical studies, particularly for neuropsychiatric illnesses with complex etiologies. Postmortem brain tissues from subjects with schizophrenia have been extensively studied, and thus serve as a useful vehicle for illustrating the challenges associated with this biological substrate. Schizophrenia is likely caused by a combination of genetic risk and environmental factors that combine to create a disease phenotype that is typically not apparent until late adolescence. The complexity of this illness creates challenges for hypothesis testing aimed at understanding the pathophysiology of the illness, as postmortem brain tissues collected from individuals with schizophrenia reflect neuroplastic changes from a lifetime of severe mental illness, as well as treatment with antipsychotic medications. While there are significant challenges with studying postmortem brain, such as the postmortem interval, it confers a translational element that is difficult to recapitulate in animal models. On the other hand, data derived from animal models typically provide specific mechanistic and behavioral measures that cannot be generated using human subjects. Convergence of these two approaches has led to important insights for understanding molecular deficits and their causes in this illness. In this review, we discuss the problem of schizophrenia, review the common challenges related to postmortem studies, discuss the application of biochemical approaches to this substrate, and present examples of postmortem schizophrenia studies that illustrate the role of the postmortem approach for generating important new leads for understanding the pathophysiology of severe mental illness.

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Section: Data From Post-synaptic Density 95 (Psd95)mentioning

confidence: 99%

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

McCullumsmith

Hammond

Shan

et al. 2013

Neuropsychopharmacol

106

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“…After three-step reactions from the intermediate, L-serine is synthesized in astrocytes and then converted into D-serine by SRR (30). Both serine enantiomers are deeply related to neurophysiology; L-serine is a neurotrophic factor essential for brain morphogenesis (31,32), whereas D-serine is a prerequisite for glutamatergic neurotransmission mediated by synaptic NMDA receptors (13,18,(33)(34)(35). Considering that L-serine is also known to control glycolytic flux through the M2 isoform of pyruvate kinase (36), neurophysiology through serine biosynthesis is inseparable from glycolysis.…”

Section: Discussionmentioning

confidence: 99%

“…SRR requires pyridoxal phosphate and also has an absolute requirement for ATP (14,15). SRR is regulated by interacting proteins, including glutamate receptor interacting protein (GRIP) (16), protein interacting with PRKCA 1 (17), disrupted in schizophrenia 1 (18), and golgin A3 (19). It is also known that the enzymatic activity of SRR is inhibited by nitric oxide in presynaptic neurons (20) and by phosphatidylinositol (4, 5)-bisphosphate (PIP2) in astrocytes (21), both of which are involved in feedback regulation via glutamate receptors.…”

mentioning

confidence: 99%

Glycolytic flux controls d -serine synthesis through glyceraldehyde-3-phosphate dehydrogenase in astrocytes

Suzuki

Sasabe

Miyoshi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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D-Serine is an essential coagonist with glutamate for stimulation of N-methyl-D-aspartate (NMDA) glutamate receptors. Although astrocytic metabolic processes are known to regulate synaptic glutamate levels, mechanisms that control D-serine levels are not well defined. Here we show that D-serine production in astrocytes is modulated by the interaction between the D-serine synthetic enzyme serine racemase (SRR) and a glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase (GAPDH). In primary cultured astrocytes, glycolysis activity was negatively correlated with D-serine level. We show that SRR interacts directly with GAPDH, and that activation of glycolysis augments this interaction. Biochemical assays using mutant forms of GAPDH with either reduced activity or reduced affinity to SRR revealed that GAPDH suppresses SRR activity by direct binding to GAPDH and through NADH, a product of GAPDH. NADH allosterically inhibits the activity of SRR by promoting the disassociation of ATP from SRR. Thus, astrocytic production of D-serine is modulated by glycolytic activity via interactions between GAPDH and SRR. We found that SRR is expressed in astrocytes in the subiculum of the human hippocampus, where neurons are known to be particularly vulnerable to loss of energy. Collectively, our findings suggest that astrocytic energy metabolism controls D-serine production, thereby influencing glutamatergic neurotransmission in the hippocampus.eurons require a great deal of energy owing to their continuous need for ion gradient restoration across the cell membrane. Recent advances in the field of brain energy metabolism strongly suggest that glutamatergic neurotransmission is coupled with molecular signals that switch on glucose utilization pathways to meet this requirement. Astrocytes are key to the energy supply for neurons through the regulation of synaptic glutamate. Astrocytic glutamate uptake drives glycolysis, as well as the subsequent shuttling of lactate from astrocytes to neurons for oxidative metabolism (1-4). Astrocytes also store brain energy currency in the form of glycogen, which can be mobilized to produce lactate for neuronal oxidative phosphorylation (OXPHOS) in response to glutamatergic neurotransmission. Inhibiting glutamate uptake in astrocytes prevents the stimulation of the glycolytic pathway mediated by glutamate (5, 6). In contrast, inhibiting glycolysis impairs glutamate transport or even releases glutamate to the extracellular space (7,8). These mechanisms suggest that glycolytic metabolism is involved in regulating synaptic glutamate levels and, consequently, in excitatory neurotransmission.N-methyl-D-aspartate (NMDA) types of glutamate receptors have principal roles in excitatory neurotransmission and participate in numerous physiological processes, including learning and memory. Activity of the NMDA receptor is tightly regulated, and its overactivation contributes to such pathological conditions as stroke (9) and neurodegenerative diseases (10-12). NMDA receptors essentially require binding of a c...

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“…However, recent data demonstrate that neurons are a main site of D-serine production and storage in the brain and that they regulate their own NMDARs by releasing D-serine (5, 8, 20 -24). Astrocytic SR is activated by interaction with a number of proteins, including Grip-1 (25), Pick-1 (26), and Disc-1 (27). Disc-1 binds to and stabilizes SR in glia cells but has no effect on neuronal SR (27).…”

mentioning

confidence: 99%

“…Astrocytic SR is activated by interaction with a number of proteins, including Grip-1 (25), Pick-1 (26), and Disc-1 (27). Disc-1 binds to and stabilizes SR in glia cells but has no effect on neuronal SR (27). Astrocytic SR is inhibited by interaction with inositol phospholipids and also by S-nitrosylation (28,29).…”

mentioning

confidence: 99%

FBXO22 Protein Is Required for Optimal Synthesis of the N-Methyl-d-Aspartate (NMDA) Receptor Coagonist d-Serine

Dikopoltsev

Foltyn

Zehl

et al. 2014

Journal of Biological Chemistry

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Background: Serine racemase produces D-serine, which is required for optimal NMDA receptor activity. Results: FBXO22 interacts with and activates serine racemase by preventing its targeting to membranes. Conclusion:The data suggest an atypical role of FBXO22 in regulating D-serine synthesis unrelated to its effects on the ubiquitin system. Significance: The results provide a new mechanism affecting D-serine synthesis with implications for the regulation of NMDA receptors.

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

Cited by 134 publications

References 76 publications

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

Glycolytic flux controls d -serine synthesis through glyceraldehyde-3-phosphate dehydrogenase in astrocytes

FBXO22 Protein Is Required for Optimal Synthesis of the N-Methyl-d-Aspartate (NMDA) Receptor Coagonist d-Serine

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