Elsevier

Neuropharmacology

Volume 62, Issue 3, March 2012, Pages 1484-1503
Neuropharmacology

Contributions of the d-serine pathway to schizophrenia

https://doi.org/10.1016/j.neuropharm.2011.01.030Get rights and content

Abstract

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’.

Highlights

► 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.

Introduction

Schizophrenia is a severe mental illness affecting approximately 1% of the population worldwide and it ranks as one of the leading causes of chronic disability (Murray et al., 1996). Symptoms of schizophrenia are generally divided into three main classes: the positive symptoms that include hallucinations, delusions and thought disorder; the negative symptoms, such as social withdrawal and blunted affect; and the cognitive symptoms, which involve profound deficits in attention, learning and memory (Ross et al., 2006, Lewis and Gonzalez-Burgos, 2006). Current treatments for this disease have limited efficacy, particularly in ameliorating the negative and cognitive symptoms, and have significant side effects that often lead to poor compliance (Ross et al., 2006, Lewis and Gonzalez-Burgos, 2006). To improve treatment and outcomes, tremendous effort has been made to uncover the neurobiological processes leading to schizophrenia.

Recent evidence indicates that schizophrenia pathophysiology involves widespread perturbations in several closely interacting neurotransmitter systems in cortical and subcortical structures (Lisman et al., 2008). Dopamine was the first neurotransmitter implicated in schizophrenia, on the basis that dopamine-releasing stimulants, such as amphetamine, can induce psychotic symptoms (Janowsky and Risch, 1979), and antipsychotic drugs reduce psychotic symptoms by the antagonism of dopamine D2 receptors (Seeman et al., 1975, Creese et al., 1976). However, the limited capacity of D2 blockade to improve negative and cognitive impairments suggests the involvement of other neurotransmitter systems, such as glutamate and γ-aminobutyric acid (GABA) (Lewis and Moghaddam, 2006).

N-methyl-d-aspartate receptor (NMDAR) hypofunction has been proposed to contribute to the pathophysiology of schizophrenia. This hypothesis was initiated by studies demonstrating that non-competitive NMDAR antagonists, such as phencyclidine or ketamine, can produce transient schizophrenia-like symptoms in healthy individuals and can exacerbate symptoms in patients (Javitt and Zukin, 1991, Krystal et al., 1994). NMDAR inhibition elicited the psychotic as well as the negative and cognitive deficits of schizophrenia (Javitt and Zukin, 1991, Krystal et al., 1994), and these effects could not be worsened by administration of dopaminergic agonists (Barch and Carter, 2005, Krystal et al., 2005). Similarly in rodents and primates, administration of NMDAR antagonists evoke a range of behavioral symptoms resembling aspects of schizophrenia (Yee et al., 2004, Lipina et al., 2005, Mandillo et al., 2003, Linn et al., 2003, Mao et al., 2008, Thompson et al., 1987, Bubeníková-Valesová et al., 2008). Transgenic mice with reduced NMDAR activity also display phenotypes relevant to schizophrenia, particularly to the negative and cognitive symptoms (Mohn et al., 1999, Labrie et al., 2008, Halene et al., 2009, Cui et al., 2004, Nakazawa et al., 2003, Niewoehner et al., 2007). Further supporting NMDAR dysfunction in schizophrenia are postmortem studies that have found numerous alterations in the binding and expression of NMDARs and NMDAR-interacting proteins in the cortex, hippocampus, thalamus, basal ganglia and cerebellum (Sokolov, 1998, Kristiansen et al., 2006, Beneyto et al., 2007, Funk et al., 2009, Toro and Deakin, 2005, Clinton and Meador-Woodruff, 2004, Clinton et al., 2006, Mueller et al., 2004, Schmitt et al., 2010). Additionally, in vivo deficits in hippocampal NMDAR binding have been observed in drug-naïve schizophrenia patients (Pilowsky et al., 2006). The success of clinical trials investigating an antipsychotic agent acting on metabotropic glutamate receptors has prompted further interest in the involvement of the glutamatergic system in schizophrenia, as it potentially represents an effective alternative to dopaminergic antipsychotics (Patil et al., 2007).

NMDAR dysfunction in schizophrenia is part of a large pathophysiological network involving a complex interplay of multiple genes, neurotransmitters and other environmental and epigenetic factors. Indeed, several risk genes for schizophrenia, including dysbindin, neuregulin and disrupted-in-schizophrenia 1 (DISC1), interact with NMDARs, affecting synaptic transmission, maturation and plasticity (Tang et al., 2009, Gu et al., 2005, Li et al., 2007, Hayashi-Takagi et al., 2010). Increases in dopamine receptor availability have been observed in the prefrontal cortex of patients with schizophrenia (Abi-Dargham et al., 2002). Similarly, chronic exposure to NMDAR antagonists has been reported to reduce extracellular dopamine levels and increase dopamine receptor binding in the prefrontal cortex of rodents, primates and humans (Jentsch et al., 1997, Tsukada et al., 2005, Narendran et al., 2005). In healthy individuals, NMDAR blockade increases amphetamine-induced dopamine release in the striatum, mimicking the exaggerated responses of schizophrenic patients to an amphetamine challenge (Kegeles et al., 2000). This suggests that deficits in NMDAR function can augment abnormalities in dopaminergic transmission in schizophrenia.

Diminished activity, synthesis and release of GABA have also been implicated in schizophrenia, as reductions in parvalbumin-immunoreactive cells (GABAergic interneurons) and the GABA synthesizing enzyme glutamic acid decarboxylase (GAD67) are common pathological findings in the cortex and hippocampus of schizophrenia patients (Torrey et al., 2005, Reynolds et al., 2004, Lewis et al., 2005, Lewis and Lieberman, 2000). A recent study using genetically-modified mice showed that early postnatal reductions of NMDAR activity on cortical and hippocampal GABAergic interneurons led to the emergence of schizophrenia-like symptoms in adulthood (Belforte et al., 2010). Interneuron-specific decreases in NMDAR signaling also resulted in diminished expression of parvalbumin and GAD67, disinhibition of cortical excitatory neurons and reduced neuronal synchrony (Belforte et al., 2010). Similar results have been observed following chronic treatment with NMDAR antagonists (Kinney et al., 2006, Homayoun and Moghaddam, 2007, Abekawa et al., 2007), indicating that decreased NMDAR activity is capable of inducing changes in the GABAergic system that are consistent with those observed in schizophrenia.

Considering the convergent evidence supporting the involvement of NMDAR hypofunction in the pathogenesis of schizophrenia, it will important to determine how aberrant NMDAR activity arises in this disease. Recent findings indicate that abnormalities in the d-serine pathway may contribute to glutamatergic dysfunction in schizophrenia. d-serine is an endogenous activator of the NMDAR that plays a central role in mediating NMDAR signaling and plasticity in the brain (Panatier et al., 2006, Mothet et al., 2000). Here, we will review evidence demonstrating that dysregulation of d-serine may contribute to aberrant NMDAR function and the pathophysiology of schizophrenia symptoms. Genetic studies have associated genes in the d-serine pathway with an increased vulnerability for schizophrenia. Neurochemical and postmortem studies in schizophrenia have found alterations in the levels of d-serine and in the expression of its regulatory enzymes. Pharmacological and genetic animal models with decreased d-serine abundance exhibit behavioral abnormalities reminiscent of the symptoms of schizophrenia. Exogenous administration of d-serine and related compounds improve several phenotypes relevant to schizophrenia in animal models and demonstrate promising clinical effects in humans. Together, these findings may improve our understanding of the molecular mechanisms involved in this complex heterogeneous disorder.

Section snippets

Modulation of the NMDAR receptor by d-serine

NMDARs are widely expressed excitatory neurotransmitter receptors in the brain that participate in a number of physiological processes, including synaptic plasticity, memory formation and development (Lynch, 2004, Escobar and Derrick, 2007). NMDARs are heteromeric protein complexes composed of at least one NR1 subunit in combination with NR2 and/or NR3 subunits (Cull-Candy et al., 2001). Multiple NR1 isoforms have been described, along with various NR2 (NR2A-D) and NR3 (NR3A and NR3B) subunits (

Genetic epidemiology

Schizophrenia has a strong genetic component, with a heritability estimate of approximately 0.8. However, the genetics are complex and no single gene displays a strong effect. Rather, schizophrenia has a heterogeneous etiology that involves multiple risk genes with modest effect sizes that interact with each other and with environmental and epigenetic factors (Harrison and Weinberger, 2005, Ross et al., 2006, Gogos and Gerber, 2006). In addition, recent findings indicate that large, rare

Animal models

Animal models can potentially be used to further the understanding of the molecular, cellular and environmental mechanisms involved in the pathogenesis of human disease and enable the development of novel therapies. However, schizophrenia is a uniquely human disease of heterogeneous origin, characterized by many prominent symptoms that are difficult to model and measure directly in animals. For example, hallucinations, thought disorder, delusions and abnormalities in perception and language can

The future of pharmacotherapies based on the d-serine pathway

Clinical trials examining the efficacy of high doses of d-serine and GlyT-1 inhibitors have shown promising effects in patients with schizophrenia. d-serine and GlyT-1 antagonists have been shown to considerably reduce positive, negative and cognitive deficits when administered in combination with antipsychotic medications (Tsai et al., 1998, Tsai et al., 2004, Heresco-Levy et al., 2005, Kantrowitz et al., 2010, Lane et al., 2008). In unmedicated schizophrenia patients, inhibition of GlyT-1 was

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      Although one study found no difference between patients with schizophrenia and controls (Fuchs et al., 2008), most studies found lower blood d-serine levels in patients with schizophrenia (Bendikov et al., 2007; Calcia et al., 2012; Hashimoto et al., 2003), a finding that was corroborated by a recent meta-analysis (Cho et al., 2016). Remarkably, variants in the gene for serine racemase, the enzyme that forms d-serine from l-serine, have also been associated with schizophrenia (Balu et al., 2013; Labrie et al., 2012). Since the link between NMDARs and schizophrenia has been established, many strategies have been tested to increase NMDAR activity, including increasing AMPA activity to indirectly activate NMDARs, the administration of glycine and d-serine, the use of glycine reuptake inhibitors, and the administration of d-cycloserine, a partial agonist at the glycine modulatory site.

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