One-carbon metabolism and schizophrenia: current challenges and future directions M.O. Krebs 1, 2 , Alfredo Bellon 1, 2 , Gaell Mainguy 1, 2 , T.M. Jay 1, 2 and Helge Frieling 1, 3 1 INSERM, Pathophysiology of Psychiatric Disorders, CPN, U894, Sainte-Anne Hospital, Paris F-75014, France 2 University Paris Descartes, Faculty of Medicine Paris Descartes, Paris, France 3 Hannover Medical School, Department of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover, Germany Schizophrenia is a heterogeneous disease generally con- sidered to result from a combination of heritable and environmental factors. Although its pathophysiology has not been fully determined, biological studies sup- port the involvement of several possible components including altered DNA methylation, abnormal glutama- tergic transmission, altered mitochondrial function, folate deficiency and high maternal homocysteine levels. Although these factors have been explored separately, they all involve one-carbon (C1) metabolism. Further- more, C1 metabolism is well positioned to integrate gene–environment interactions by influencing epige- netic regulation. Here, we discuss the potential roles of C1 metabolism in the pathophysiology of schizo- phrenia. Understanding the contribution of these mech- anisms could yield new therapeutic approaches aiming to counteract disease onset or progression. Introduction Schizophrenia is a complex and disabling disorder that appears during adolescence or young adulthood [1]. The prevalence of schizophrenia is approximately 1% (six times more than that of insulin-dependent diabetes) and 1/4000 new cases are diagnosed each year worldwide (i.e. 100 000 new cases per year in the US). Schizophrenia ranks among the top 10 causes of disability in developed countries worldwide. It has dramatic consequences for affected indi- viduals, causing considerable familial and social burden. The phenotype is variable between patients and through- out the course of the disease. It comprises ‘‘positive’’ (hal- lucinations, delusions) and ‘‘negative’’ (lack of motivation and energy, poor social interaction) symptoms, as well as disorganized speech and behavior and affective symptoms (anhedonia, depression). Cognitive deficits are also associ- ated and are the main source of social burden and poor quality of life. Although many questions remain unanswered, progress has been made in understanding the pathophysiology of schizophrenia. The dopamine hypothesis first emerged in relation to pharmacological evidence – specifically the ability of antidopaminergic compounds to reverse psycho- tic symptoms [1]. These compounds, the antipsychotics, are still the gold standard for treating schizophrenia despite limited success in treating negative symptoms and their side effect profile. Drug development strategies seek to discover pathophysiological pathways that could reduce cognitive and negative symptoms [2,3] and limit or avoid the progression of the disease [4]. Interestingly, a recent study suggests that the onset of psychosis is associated with gray matter reduction in several brain areas [5]. The mechanism of this reduction is undetermined but it could be indicative of maturational changes and/or neurotoxicity occurring during onset. Beyond the dopamine hypothesis, several non-exclusive hypotheses have emerged based on epidemiological, postmortem, genetic, brain imaging or experimental studies in human or animal models. It is beyond the scope of this review to discuss all the hypoth- eses supported by current literature and extended critical reviews have recently been published [6,7]. Here, we will focus on four hypotheses that have been independently implicated in schizophrenia and discuss the data that connect them to C1 metabolism. These four hypotheses are briefly presented below. Opinion Glossary Apoptosis: programmed cell death. Complex IV (or cytochrome c oxidase enzyme): is the last enzyme in the mitochondrial respiratory electron transport chain. Epigenetic: heritable changes in gene expression that occur without modifica- tions in the sequence of DNA. Several biological processes are involved, including the methylation of DNA or histones. Histone: protein that is the main component of chromatin, which plays a role in gene regulation. Metabolomics: large-scale studies identifying and quantifying metabolites in a given biological context. Proteomics: large-scale studies of structures, functions and expression patterns of proteins in a given biological context. Transcriptomics: large-scale study of messenger RNA (mRNA) molecules in a given biological context. Reactive oxygen species (ROS): small molecules that include oxygen ions, free radicals and peroxides that are highly reactive. ROS levels can increase dramatically, which can result in significant damage to cell structures. Single nucleotide polymorphism (SNP): modification of the sequence of the DNA observed between individuals of the same species. The polymorphisms can be synonymous (protein sequence not modified) or not (missense). Psychosis: a group of psychiatric disorders in which psychotic symptoms are present (disorganized thought or behavior, unusual thought content, percep- tual anomalies). Major psychosis comprises schizophrenia, bipolar disorders with psychotic characteristics, schizo-affective disorder, paranoia, brief psychotic disorders and/or schizophreniform disorders. Childhood onset psychosis disorders include autism, Asperger syndrome and pervasive development disorders. Corresponding author: Krebs, M.O. (Marie-Odile.krebs@inserm.fr). 562 1471-4914/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.molmed.2009.10.001 Available online 5 November 2009