1. Epigenetic Study Aims to Reveal Etiology of Schizophrenia
Marissa Cohen1
& Katherine Kenneweg2
1
Dept. of Zoology, Miami University, Oxford, Ohio; 2
Dept. of Microbiology, Miami University, Oxford, Ohio
What is Epigenetics?
GABA
Gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the mammalian
central nervous system. Glutamic acid decarboxylase (GAD) is responsible for the conversion of
glutamate to GABA, and is the limiting factor in regulating levels of CNS GABA. In several brain
sites, GAD67 is colocalized to the same GABAergic interneurons as Reelin (RELN), an extracellular
matrix protein that subserves synaptic plasticity in adult brain and that helps in normal lamination of
the embryonic brain. Recent studies have shown that the genes that encode reelin and GAD67 are
downregulated at both transcriptional and translational levels in the schizophrenic brain. These
downregulations are believed to be caused by increases in methylation at the promoter of each gene
regulated by DNA Methyltransferase 1 (DNMT), which is upregulated in GABAergic interneurons.
Furthermore, the promoters of RELN and GAD67 are embedded within CpG islands, areas of DNA
known to be epigenetically regulated by hypermethylation. (Costa, Grayson, & Guidotti, 2003)
Understanding epigenetic mechanisms regulating RELN and GAD67 transcription is likely to lead
to the discovery of new drugs able to reprogram transcriptional programs that support
neuropathology. Thus, inhibiting DNMT activity in schizophrenics along the RELN or GAD67
promoters should decrease schizophrenic symptoms, but the lack of specific DNMT inhibitors
prevents further investigation of this hypothesis. However, because histone deacetylase (HDAC)
interacts with DNMT to inactivate chromatin, HDAC inhibitors can be used to prevent DNMT activity.
The HDAC inhibitor, valproate, has shown to lead to an increase in histone acetylation, thereby
counteracting the effects of DNMT. (Roth, Lubin, Sodhi, & J.E., 2009)
Histone Modification
Several recent research studies have found significant
differences in postmortem brains in histone modifications when
compared to brains from individuals who did not suffer from
schizophrenia. In particular, elevated levels of enzyme histone
deacetylase 1, HDAC1, has been found in diseased samples as
well as decreased levels of GAD67. Further, at the GAD67
promoter, lower H3K4 methylation has been observed, thus
lowering GAD67 expression. In general, HDAC has been shown
to improve neurodegenerative and cognitive phenotypes, boost
memory and learning tasks, and lower ischemic damage in wild
type mice. More specifically, HDAC1 negatively mediated by
siRNA or by pharmacological means has resulted in increased
cell death and impaired learning in studies. Normally, HDAC1
corrects DNA damage and prevents ischemic cell death, thus
indicating that the pathogenic processes included in
schizophrenia increase HDAC1 expression and the disorder is
propagated by the increase. Common antidepressants used to
treat schizophrenia able to alter the chromatin, are known to
alleviate some of the symptoms of the disorder. These MAOIs
have H3K4 histone demethylase inhibitory activity, thus
indicating that H3K4 methylation may be integral to
schizophrenia development. Other histone modifications
including in methylated lysines in H3K27 and dimethylated
H3K9, methylated arginine in H3R17, and phosphorylated
serine and acetylated acetylation in H3S10K14, show significant
differences from normal brains are currently undergoing further
study. Researchers are now utilizing peripheral blood
mononuclear cells to investigate global DNA methylation levels
(Gavin & Shrama, 2009).
Effects of Environment
Epigenetic modifications are caused by environmental conditions, both neonatal and postnatal.
Significant research has been done to investigate these effects and possible contributions to
diseases such as schizophrenia in the hope that finding these correlations will lead to better disease
prevention in the future. One study investigating the effect of maternal nutrition found that famine
conditions for the mother could increase risk of schizophrenia for the fetus in utero two-fold. Thus,
malnutrition may trigger gene misregulation and differential methylation. Another possible cause of
epigenetic changes may be parental rearing. Rat studies found that maternal grooming of pups
caused methylation and histone modifications in the glucocorticoid receptor gene promoter in the
hippocampus, which is involved in memory, emotion, navigation, and spatial orientation, all of which
are areas of interest to schizophrenia researchers.
Researchers have also studied the effect of drug use and environmental pressures such as
stress. DNMT1 expression has been found to change and cause schizophrenia-like symptoms in
chronic methanphetamine users. Cocaine use has been linked to unusual histone acetylation
resulting from decreased HDAC activity, as have cannabis and the mood stabilizer and
anticonvulsant valproate. Finally, fear and stress revealed demethylation and increased expression
of RELN., The increased stress of urbanicity has shown higher incidence of schizophrenia when
compared to rural areas. (Oh, 2008).
What is Schizophrenia?
Schizophrenia is a chronic psychotic disorder characterized by
disturbed perceptions, emotions, behavior and thinking. There are
approximately 2 million affected individuals in the United States,
about 1% of the population, with a worldwide estimate is 24 million.
Occurrance is fourfold higher in men. There are three main
categories of schizophrenia – disorganized type, catatonic type,
and paranoid type. These categories all have some overlapping
clinical features including delusions, thought disorder,
hallucinations, inappropriate or flat emotions, difficulty screening
environmental stimuli, impaired social interaction skills, and
personal identity uncertainty. The DSM-IV-TR has 4 diagnostic
contentions. The first set is symptomatically based. Next, the
individual’s occupation, relationships, or self-care is markedly
different from prior to disorder onset. The affected period must
extend at least six months, and a change in behaviors and thoughts
leading to diagnosis cannot be the result of another medical
condition or substance (Nevid, 2008).
Studies done with monozygotic twins yielded concordance
rates of 48% and 3.6% in dizygotic twins (Gottesman, 1991). These
values support the conclusion that there is a significant genetic
cause of schizophrenia, but that environmental factors contribute to
the disorder, as well. This is further supported by research which
reported that children of two schizophrenic parents had only a 45%
chance of developing schizophrenia themselves.
Though one cause of schizophrenia has not been identified,
researchers have suggested viral, genetic, nutritional,
neurotransmitter changes, and brain mass decrease (Brown, Begg,
Gravenstein, Schaefer, Wyatt, Bresnahan, et al., 2004). There is no
treatment for schizophrenia, although antipsychotic medications
can reduce symptoms. Researchers hope to find the etiology of the
disorder in order to find a cure for schizophrenia.
References
Brown, AS, Begg, MD, Gravenstein, S, Schaefer, CA, Wyatt, RJ. Bresnahan, M, et al. (2004). Serological evidence of prenatal influenza in the etiology of
schizophrenia. Archives of Gen. Psychiatry. 61, 774-780
Costa, E, Grayson, D, & Guidotti, A. (2003). Epigenetic functions in schizophrenia. Molecular interventions, 220-229.
Gavin, DP & Sharma, RP. (2009). Histone modifications, DNA methylation, and Schizophrenia. Neuroscience and Biobehavioral Reviews 34, 882-888
Fatemi, H, Stary, J, Earle, J, Araghi-Niknam, M, & Eagan, E. (2005). GABAergic dysfunction in schizophrenia and mood disorders as feflected by decreased
levels of gluamic acid decarboxylase 65 and 67 kDa and Reelin proteins in cerebellum. Schizophrenia Research , 109-122.
Gottesman, II. (1991). Schizophrenia genetics: The origins of madness. New York: Freeman.
Narr, KL, Thompson, PM, Sharma, T, Moussai, J, Cannestra, AF, Toga, AW. (2000). Mapping Corpus Callosum Morphology in Schizophrenia. Cerebral
Cortex. 10(1), 40-49.
Nevid, JS, Rathus, SA, and Greene, B. (2008). Abnormal Psychology in a Changing World: Seventh edition.
Oh, G and Petronis, A. (2008). Environmental Studies of Schizophrenia Through the Prism of Epigenetics. Schizophr. Bull. 34(6), 1122-1129.
Roth, T, Lubin, F, Sodhi, M, and JE, K. (2009). Epigenetic mechanisms in schizophrenia. Biochimica et Biophysica Acta , 869-877.
Thompson, PM, Vidal, C, Giedd, JN, Gochman, P, Blumenthal, J, Nicolson, R, Toga, AW, and Rapoport, JL. (2001). Mapping adolescent brain change
reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. PNAS. 11650-11655.
“The difference between genetics and epigenetics can probably be
compared to the difference between writing and reading a book.
Once a book is written, the text (the genes or DNA: stored
information) will be the same in all the copies distributed to the
interested audience. However, each individual reader of a given
book may interpret the story slightly differently, with varying emotions
and projections as they continue to unfold the chapters. In a very
similar manner, epigenetics would allow different interpretations of a
fixed template (the book or genetic code) and result in different read-
outs, dependent upon the variable conditions under which this
template is interrogated.”
- Thomas Jenuwein (Vienna, Austria)
(Thompson, et. al., 2001) (Narr, et al., 2000)
Background image courtesy of The Royal Society of New Zealand
(http://nihroadmap.nih.gov/EPIGENOMICS/images/epigeneticmechanisms)
Conclusions
Recent research provides evidence that although schizophrenia
is affected by genetics, epigenetics play a major role in the
development of the disorder, as well. Environmental conditions an
individual encounters during his life both in his mother’s womb and
after birth lead to methylation, acetylation, and phosphorylation of
DNA and histone tails. These modifications, though normal, may
lead to severe consequences if done in specific areas of the brain
and within certain genes. Methylation of the promoters of certain
genes, such as GAD67, are obvious causes of schizophrenia.
Emerging neurobiological evidence indicates that many of the genes
potentially involved in etiology of schizophrenia may also be involved
in pathology of bipolar disorder and to a lesser degree in major
depression and other neurodevelopmental disorders like autism
(Fatemi, Stary, Earle, Araghi-Niknam, & Eagan, 2005). By studying
the major epigenetic mechanisms implicated in schizophrenia and
these other disorders, it seems we are paving a road toward
treatment and prevention.