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The epigenetics of schizophrenia is the study of how the inherited genetic code is regulated and modified by the environment and external factors through molecular mechanisms, and how these changes shape and influence the onset and development of, and vulnerability to the psychological and neurological disorder, schizophrenia. Epigenetics also studies how these genetic modifications can be passed on to future generations. Schizophrenia is a debilitating and misunderstood disorder that affects up to 1% of the world's population^[1]. While schizophrenia is a historically well studied disorder, epigenetics offers a new avenue for research, understanding, and treatment.

Historically, schizophrenia has been studied and examined through different paradigms, or schools of thought. In the late 1870s, Emil Kraeplin started the idea of studying it as an illness. Another paradigm, introduced by Zubin and Spring in 1977, was the stress-vulnerability model where the individual has unique characteristics that gives him or her strengths or vulnerabilities to deal with stress, a predisposition for schizophrenia. More recently, with the decoding of the human genome, there has been the focus on identifying specific genes to study the disease. However, the genetics paradigm faced problems with inconsistent, inconclusive, and variable results. The most recent school of thought is studying schizophrenia through epigenetics ^[2].

The idea of epigenetics has been described as far back as 1942, when Conrad Waddington described it as how the environment regulated genetics. As the field and available technology has progressed, the term has come to also refer to the molecular mechanisms of regulation. The concept that these epigenetic changes can be passed on has progressively come to be more accepted ^[3].

The core symptoms of schizophrenia can be classified into three broad categories. These symptoms are often used to build schizophrenic animal and behavioral models when studying epigenetics. ^[1]. Positive symptoms are considered limbic system aberrations, while negative and cognitive symptoms are thought of as frontal lobe abnormalities ^[4].

Positive Symptoms:

• Hallucination
• Delusions and paranoia
• Thought disorders

Negative Symptoms:

• Apathy
• Poverty of speech
• Flat or blunted emotions

Cognitive Dysfunctions:

• Impaired working memory
• Disorganized thoughts
• Cognitive impairments^[1]

There is a great deal of evidence to show that schizophrenia is a heritable disease. Twin studies have shown that the likelihood of developing the disease is 53% for one member of monozygotic twins (twins with same genetic code), compared to the 15% for dizygotic twins, who don't share the exact DNA ^[5].

The fact that even monozygotic twins don't share a 100% concordance rate suggests environmental factors play a role in the vulnerability and development of the disorder. There are various environmental factors that have been suggested in various studies, including the use of marijuana, complications during pregnancy, socioeconomic status and environment, and maternal malnutrition. As the field of epigenetics advances, these and other external risk factors are likely to be considered in epidemiological studies ^[1].

Several genes have been identified as important in the study of schizophrenia, but there are a few that have special roles when studying the epigenetic modifications of the disease.

• GAD1- GAD1 codes for the protein GAD67, an enzyme that catalyzes the formation of GABA from glutamate. Schizophrenics have shown a decrease in GAD67 levels and this deficit is thought to lead to working memory problems, among other impairments ^[6]
• RELN- RELN codes for reelin, an extracellular protein that is necessary for formation of memories and learning through plasticity. Reelin is thought to regulate nearby glutamate producing neurons^[1].

Both proteins are created by GABAergic neurons. Several studies have demonstrated that levels of both reelin and GAD67 are downregulated in schizophrenic patients and animal models.

• BDNF - Brain-derived neurotrophic factor, BDNF, is another important gene in the study of schizophrenia genetics. BDNF plays a crucial role in cognition, learning, memory formation, and vulnerability to social and life experiences ^[1].

Epigenetics can be studies and researched through various methods. One of the most common methods is looking at postmortem brain tissue of schizophrenic patients and analyzing them for biomarkers. Other common methods include tissue culture studies of neurons, genome-wide analysis of non-brain cells in living patients (see PBMC), and transgenic and schizophrenic animal models ^[1].

Other studies that are currently being done or that can be done in the future include longitudinal studies of patients, "at-risk" populations, and monozygotic twins, and studies that examine specific gene-environment interactions and epigenetic effects ^[7].

Epigenetics is the study of changes in the genetic code that can be inherited.

Methylation of DNA is done by the addition of a methyl group to CpG islands in the DNA. This leads to a constriction of the chromosome and silencing of the gene by preventing transcription.

Histones are proteins that DNA chromosome are wrapped around. Histones can be activated or deactivated, leading to the opening of transcription sites.

Studies have shown that epigenetic changes can be passed on to future generations through meiosis and mitotis ^[8]. These findings suggest that environmental factors that the parents face can possibly affect how the child's genetic code is regulated. Research findings have shown this to tbe true for schizophrenic patients as well. In rats, the transmission of maternal behavior and even stress responses can be attributed to how certain genes in the hippocampus of the mother are methylated ^[1]. Another study has shown that the methlyation of the BDNF gene, which can be affected by early life stress and abuse, is also transmittable to future generations ^[9].

While there haven't been many studies linking environmental factors to schizophrenia-related epigenetics mechanisms, a few have shown interesting results. Advanced paternal age is one of the risk factors for schizophrenia, according to recent research. This is through mutagenesis, which cause further spontaneous changes, or through genomic imprinting. As the parent ages, more and more errors may occur in the epigenetic process ^[10]. There is also evidence of the association between the inhalation of benzene through the burning of wood and schizophrenic development. This might occur through epigenetic changes ^[11]. Methamphetamine has also been to linked to causing schizophrenia or similar psychotic symptoms. A recent study found that methamphetamine users had altered DNMT1 levels, similar to how schizophrenic patients have shown abnormal levels of DNMT1 in GABAergic neurons ^[12]. Recent scientific findings have shown that there some links between the use of cannabis and the development of schizophrenia through family and medical studies. Epigenetic mechanisms haven't yet been examined for marijuana however. ^[13].

There are several limitations to current research methods and scientific findings. One problem with postmortem studies is that they only demonstrate a single snapshot of a schizophrenic patient. Thus, it is hard to relate whether biomarker findings are related to the pathology of schizophrenia.

Another limitation is that the most relevant tissue, that of the brain, is impossible to obtain in living, schizophrenic patients. To work around this, several studies have used more accessible sources, like lymphocytes or germ cell lines, since some studies have shown that epigenetic mutations can be detected in other tissues.

Epigenetic studies of disorders like schizophrenia are also subject to the subjectivity of psychiatric diagnoses and the spectrum-like nature of mental health problems. This problem with classification of mental health problems have led to intermediate phenotypes that might be better fit ^[7].

• Epigenetics
• Neuroscience
• Behavioral epigenetics
• Epigenetics in psychology
• Schizophrenia

• Science: Special Online Collection: Epigenetics. http://www.sciencemag.org/site/special/epigenetics/index.xhtml
• Akbarian, S. Epigenetics of Schizophrenia. Current Topics in Behavioral Neurosciences Volume 4, 2010, pp 611-628
• Gavin, D.P., Sharma, R. P., Histone Modifications, DNA Methylation, and Schizophrenia. Neurosci Biobehav Rev. 2010 May; 34 (6): 882-888
• Petronis, A., Mill, J., Brain, Behavior, and Epigenetics. 2011 May. Springer. London
• Petronis, A., Oh, G., Environmental Studies of Schizophrenia Through the Prism of Epigenetics. Schizophrenic Bulletin. 2008 August.
• Roth, T.L.,Lubin, F.D., Epigenetic Mechanisms in Schizophrenia. Biochimica et Biophysica Acta. 2009 June

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