Contributions of the d-serine pathway to schizophrenia

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The glutamate neurotransmitter system is one of the major candidate pathways for the pathophysiology of schizophrenia, and increased understanding of the pharmacology, molecular biology and biochemistry of this system may lead to novel treatments. Glutamatergic hypofunction, particularly at the NMDA receptor, has been hypothesized to underlie many of the symptoms of schizophrenia, including psychosis, negative symptoms and cognitive impairment. This review will focus on d-serine, a co-agonist at the NMDA receptor that in combination with glutamate, is required for full activation of this ion channel receptor. Evidence implicating d-serine, NMDA receptors and related molecules, such as d-amino acid oxidase (DAO), G72 and serine racemase (SRR), in the etiology or pathophysiology of schizophrenia is discussed, including knowledge gained from mouse models with altered d-serine pathway genes and from preliminary clinical trials with d-serine itself or compounds modulating the d-serine pathway. Abnormalities in d-serine availability may underlie glutamatergic dysfunction in schizophrenia, and the development of new treatments acting through the d-serine pathway may significantly improve outcomes for many schizophrenia patients.

This article is part of a Special Issue entitled ‘Schizophrenia’.


▸ This review describes the role of the d-serine pathway in schizophrenia pathogenesis. ▸ Genetic studies associate genes regulating d-serine availability with increased schizophrenia risk. ▸ Postmortem schizophrenia studies observe abnormalities in d-serine modulatory enzymes. ▸ In vivo findings report altered levels of endogenous NMDA receptor co-agonist site ligands in schizophrenia. ▸ Genetic animal models with aberrant NMDA receptor co-agonist site function display schizophrenia-like symptoms.

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