In the history of biology, preformationism (or preformism) is a formerly popular theory that organisms develop from miniature versions of themselves. Instead of assembly from parts, preformationists believed that the form of living things exist, in real terms, prior to their development. Preformationists suggested that all organisms were created at the same time, and that succeeding generations grow from homunculi, or animalcules, that have existed since the beginning of creation, which is typically defined by religious beliefs.
Epigenesis (or neoformism),
then, in this context, is the denial of preformationism: the idea that,
in some sense, the form of living things comes into existence. As
opposed to "strict" preformationism, it is the notion that "each embryo
or organism is gradually produced from an undifferentiated mass by a
series of steps and stages during which new parts are added" (Magner
2002, p. 154).
This word is still used in a more modern sense, to refer to those
aspects of the generation of form during ontogeny that are not strictly
genetic, or, in other words, epigenetic.
Apart from those distinctions (preformationism-epigenesis and genetic-epigenetic), the terms preformistic development, epigenetic development and somatic embryogenesis are also used in another context, in relation to the differentiation of a distinct germ cell
line. In preformistic development, the germ line is present since early
development. In epigenetic development, the germ line is present, but
it appears late. In somatic embryogenesis, a distinct germ line is
lacking. Some authors call Weismannist development (either preformistic or epigenetic) that in which there is a distinct germ line.
Pythagoras
is one of the earliest thinkers credited with ideas about the origin of
form in the biological production of offspring. It is said[7]
that he originated "spermism", the doctrine that fathers contribute the
essential characteristics of their offspring while mothers contribute
only a material substrate. Aristotle
accepted and elaborated this idea, and his writings are the vector that
transmitted it to later Europeans. Aristotle purported to analyse
ontogeny in terms of the material, formal, efficient, and teleological
causes (as they are usually named by later anglophone philosophy) – a
view that, though more complex than some subsequent ones, is essentially
more epigenetic than preformationist. Later, European physicians such
as Galen, Realdo Colombo and Girolamo Fabrici would build upon Aristotle's theories, which were prevalent well into the 17th century.
In 1651, William Harvey published On the Generation of Animals (Exercitationes de Generatione Animalium), a seminal work on embryology that contradicted many of Aristotle's fundamental ideas on the matter. Harvey famously asserted, for example, that ex ovo omnia—all
animals come from eggs. Because of this assertion in particular, Harvey
is often credited with being the father of ovist preformationism.
However, Harvey's ideas about the process of development were
fundamentally epigenesist. As gametes
(male sperm and female ova) were too small to be seen under the best
magnification at the time, Harvey's account of fertilization was
theoretical rather than descriptive. Although he once postulated a
"spiritous substance" that exerted its effect on the female body, he
later rejected it as superfluous and thus unscientific. He guessed
instead that fertilization occurred through a mysterious transference by
contact, or contagion.
Harvey's epigenesis, more mechanistic and less vitalist than the Aristotelian version, was, thus, more compatible with the natural philosophy of the time. Still, the idea that unorganized matter could ultimately self-organize into life challenged the mechanistic framework of Cartesianism, which had become dominant in the Scientific Revolution. Because of technological limitations, there was no available mechanical explanation for epigenesis.
It was simpler and more convenient to postulate preformed miniature
organisms that expanded in accordance with mechanical laws. So
convincing was this explanation that some naturalists claimed to
actually see miniature preformed animals (animalcules) in eggs and miniature plants in seeds. In the case of humans, the term homunculus was used.
Elaboration
After the discovery of spermatozoa in 1677 by Dutch microscopist Antonie van Leeuwenhoek,
the epigenist theory proved more difficult to defend: How could complex
organisms such as human beings develop from such simple organisms?
Thereafter, Giuseppe degli Aromatari and then Marcello Malpighi and Jan Swammerdam
made observations using microscopes in the late 17th century, and
interpreted their findings to develop the preformationist theory. For
two centuries, until the development of cell theory,
preformationists would oppose epigenicists, and, inside the
preformationist camp, spermists (who claimed the homunculus must come
from the man) to ovists, who located the homunculus in the ova.
Dutch microscopist Antonie van Leeuwenhoek
was one of the first to observe spermatozoa. He described the
spermatozoa of about 30 species, and thought he saw in semen "all manner
of great and small vessels, so various and so numerous that I do not
doubt that they be nerves, arteries and veins...And when I saw them, I
felt convinced that, in no full grown body, are there any vessels which
may not be found likewise in semen." (Friedman 76-7)
Leeuwenhoek discovered that the origin of semen was the testicles
and was a committed preformationist and spermist. He reasoned that the
movement of spermatozoa was evidence of animal life, which presumed a
complex structure and, for human sperm, a soul. (Friedman 79)
In 1694, Nicolaas Hartsoeker, in his Essai de Dioptrique
concerning things large and small that could be seen with optical
lenses, produced an image of a tiny human form curled up inside the
sperm, which he referred to in the French as petit l'infant and le petit animal. This image, depicting what historians now refer to as the homunculus,
has become iconic of the theory of preformationism, and appears in
almost every textbook concerning the history of embryological science.
Philosopher Nicolas Malebranche was the first to advance the hypothesis that each embryo could contain even smaller embryos ad infinitum, like a Matryoshka doll.
According to Malebranche, "an infinite series of plants and animals
were contained within the seed or the egg, but only naturalists with
sufficient skill and experience could detect their presence." (Magner
158-9)
In fact, Malebranche only alleged this, observing that if microscopes
enabled us to see very little animals and plants, maybe even smaller
creatures could exist. He claimed that it was not unreasonable to
believe that "they are infinite trees in only one seed," as he stated
that we could already see chickens in eggs, tulips in bulbs, frogs in
eggs. From this, he hypothesized that "all the bodies of humans and
animals," already born and yet to be born, "were perhaps produced as
soon as the creation of the world."
Ova were known in some non-mammalian species, and semen was thought to spur the development of the preformed organism contained therein. The theory that located the homonculus in the egg was called ovism. But, when spermatozoa were discovered, a rival camp of spermists sprang up, claiming that the homunculus must come from the male. In fact, the term "spermatozoon," coined by Karl Ernst von Baer, means "seed animals."
With the discovery of sperm and the concept of spermism came a
religious quandary. Why would so many little animals be wasted with each
ejaculation of semen? Pierre Lyonet said the wastage proved that sperm could not be the seeds of life. Leibniz supported a theory called panspermism
that the wasted sperm might actually be scattered (for example, by the
wind) and generate life wherever they found a suitable host.
Leibniz also believed that “death is only a transformation
enveloped through diminution,” meaning that not only have organisms
always existed in their living form, but that they will always exist,
body united to soul, even past apparent death.
In the 18th century, some animalculists thought that an animal's
sperm behaved like the adult animal, and recorded such observations.
Some, but not all, preformationists at this time claimed to see
miniature organisms inside the sex cells. But, about this time,
spermists began to use more abstract arguments to support their
theories.
Jean Astruc,
noting that parents of both sexes seemed to influence the
characteristics of their offspring, suggested that the animalcule came
from the sperm and was then shaped as it passed into the egg. Buffon and Pierre Louis Moreau also advocated theories to explain this phenomenon.
Preformationism, especially ovism, was the dominant theory of generation during the 18th century. It competed with spontaneous generation and epigenesis, but those two theories were often rejected on the grounds that inert matter could not produce life without God's intervention.
Some animals' regenerative capabilities challenged preformationism, and Abraham Trembley's studies of the hydra convinced various authorities to reject their former views.
Lazaro Spallanzani,
Trembley's nephew, experimented with regeneration and semen, but failed
to discern the importance of spermatozoa, dismissing them as parasitic
worms and concluding instead that it was the liquid portion of semen
that caused the preformed organism in the ovum to develop.
Criticisms and cell theory
Caspar Friedrich Wolff,
an epigeneticist, was an 18th-century exception who argued for
objectivity and freedom from religious influence on scientific
questions.
Despite careful observation of developing embryos, epigenesis
suffered from a lack of a theoretical mechanism of generation. Wolff
proposed an "essential force" as the agent of change, and Immanuel Kant with Johann Friedrich Blumenbach proposed a "developing drive" or Bildungstrieb, a concept related to self-organization.
Naturalists of the late 18th century and the 19th century
embraced Wolff's philosophy, but primarily because they rejected the
application of mechanistic development, as seen in the expansion of
miniature organisms. It was not until the late 19th century that
preformationism was discarded in the face of cell theory.
Now, scientists "realized that they need not treat living organisms as
machines, nor give up all hope of ever explaining the mechanisms that
govern living beings." (Magner 173)
When John Dalton's atomic theory of matter superseded Descartes' philosophy of infinite divisibility
at the beginning of the 19th century, preformationism was struck a
further blow. There was not enough space at the bottom of the spectrum
to accommodate infinitely stacked animalcules, without bumping into the
constituent parts of matter. (Gee 43)
Roux and Driesch
Near the end of the 19th century, the most prominent advocates of preformationatism and epigenesis were Wilhelm Roux and Hans Driesch. Driesch's experiments on the development of the embryos of sea urchins are considered to have been decisively in favor of epigenesis.
The epigenetics of schizophrenia is the study of how inherited epigenetic
changes are regulated and modified by the environment and external
factors and how these changes influence the onset and development of,
and vulnerability to, schizophrenia.
Epigenetics concerns the heritability of those changes, too.
Schizophrenia is a debilitating and often misunderstood disorder that
affects up to 1% of the world's population.
Although schizophrenia is a heavily studied disorder, it has remained
largely impervious to scientific understanding; epigenetics offers a new
avenue for research, understanding, and treatment.
Background
History
Historically,
schizophrenia has been studied and examined through different
paradigms, or schools of thought. In the late 1870s, Emil Kraepelin 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 give him or her
strengths or vulnerabilities to deal with stress, a predisposition for
schizophrenia. More recently, with the decoding of the human genome,
there had been a 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.
A visualization of the stress-vulnerability model, also known as the diathesis-stress model
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 to future
generations has progressively become more accepted.
While epigenetics is a relatively new field of study, specific
applications and focus on mental disorders like schizophrenia is an even
more recent area of research.
Schizophrenia
Symptoms
The
core symptoms of schizophrenia can be classified into three broad
categories. These symptoms are often used to build and study animal models of schizophrenia in the field of epigenetics. Positive symptoms are considered limbic system aberrations, while negative and cognitive symptoms are thought of as frontal lobe abnormalities.
Positive symptoms:
The limbic system and associated structures of the brain, where abnormalities lead to positive symptoms of schizophrenia
Heritability
represents the percentage in variability in a trait that comes from
genetic differences. There is a great deal of evidence to show that
schizophrenia is a heritable disease. It has been calculated that the
heritability of schizophrenia is around 80%, and within that
heritability 30% of the variability comes from single nucleotide
polymorphisms and another 30% from large copy number variants
(CNVs). One key piece of evidence is a twin study that showed 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.
It has also been shown that having direct family members that are
diagnosed with schizophrenia increases the rate of developing
schizophrenia by 9 times. Another study investigated the rates of
schizophrenia of adoptees: adoptees with a genetic history of
schizophrenia that were adopted by non-schizophrenic parents were seen
to be diagnosed with schizophrenia at higher rates than adoptees without
a biological history of schizophrenia but raised with adoptive parents
diagnosed with schizophrenia.
However, the extent to which interactions between environmental and
genetic factors contribute to the development of schizophrenia is
uncertain. Others question the evidence of heritability due to different
definitions of schizophrenia and the similar environment for both
twins.That said, 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.
Maternal immune responses are involved in schizophrenia
development. A 2019 study found that, in mice models, maternal immune
activation may be involved in the regulation of the ARX gene expression
that contributes to the GABA dysfunction commonly implicated in
schizophrenia.
Most maternal effects involved in schizophrenia development have to do
with immune system activation and associated cytokine and neurogenesis
mechanisms rather than genetic changes.
Paternal genetic effects are seen to be involved in the rate of
development of schizophrenia. A 2021 study showed that advanced paternal
age was associated with higher schizophrenia risk. In the study, the
paternal ages were grouped into 5-year increments, and it was seen that
as the increments increased, so did the risk of developing
schizophrenia.
It is hypothesized that advanced paternal age increases schizophrenia
risk because fathers pass down three to four times more de novo
mutations than do mothers.
It is estimated that 2 new de novo mutations are created a year,
resulting in fathers with an advanced age passing down more mutations to
their offspring, which may explain the increased rates of schizophrenia.
There are various environmental factors that have been suggested,
including the use of marijuana, complications during pregnancy,
socioeconomic status and environment, and maternal malnutrition. In some
circumstances, it has been shown that environmental factors can
increase the risk of schizophrenia when combined with a family history
of psychosis.
As the field of epigenetics advances, these and other external risk
factors are likely to be considered in epidemiological studies.
Genes associated with schizophrenia
Among
the many genes known to be associated with schizophrenia, a few have
been identified as particularly important when studying the epigenetic
phenomena underlying the disease.
GAD1 – GAD1 codes for the proteinGAD67, an enzyme that catalyzes the formation of GABA from glutamate.
Individuals with schizophrenia have shown a decrease in GAD67 levels
and this deficit is thought to lead to working memory problems, among
other impairments.
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.
Both proteins are expressed by GABAergic neurons. Several studies
have demonstrated that levels of both reelin and GAD67 are downregulated
in patients with schizophrenia 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.
Genome-wide association studies (GWAS) have confirmed the presence of other genes thought to be involved in the regulation of schizophrenia.
Several genes that GWAS have determined to be associated with
schizophrenia include genes involved in neurodevelopment, including
glutamatergic signaling, synaptic transmission, and the regulation of
voltage-gated calcium channels.
This includes the GAD1 and RELN pathways denoted above as well as BDNF.
Another important gene is the Dopamine Receptor 2 gene, which encodes a
dopamine receptor (D2), a primary target of many of the antipsychotic
drugs that are used to treat patients with schizophrenia. Chromosomal regions containing a large number of CNVs are reported to lead to increased susceptibility to schizophrenia.
Copy number variants
(CNVs) have also been reported to be associated with schizophrenia,
particularly in chromosomal regions with large amounts of CNVs.
A CNV located at the gene NRXN1, which encodes a neurexin protein
involved in synaptic transmission, is thought to cause a
loss-of-function mutation that is associated with the development of
schizophrenia.
Loss-of-function mutations at the gene encoding histone H3
methyltransferase, an important enzyme for epigenetic histone
modification, have also been implicated in gene-association studies for
schizophrenia.
Histone modification is not the only epigenetic mechanism thought to be
commonly associated with schizophrenia. Analyzing
schizophrenia-associated genes reveals that risk loci are commonly found
near DNA methylation quantitative trait loci (which affect CpG
methylation), which have post-transcriptional modifications uniquely
correlated to schizophrenia and produce splice variants with strong
chromatin associations.
DNA methylation, post-transcriptional modification and splice
variation, and chromatin modifications are all prominent epigenetic
mechanisms, and their association with schizophrenia-risk-associated
loci indicates that these mechanisms may play a significant role in the
development of the disease.
Moving away from GWAS, linkage studies
have proved to be unsuccessful due to the interaction of several
different genes that are all involved in the development of
schizophrenia.
There are also few specific SNPs majorly involved in the development of
schizophrenia, however groups of SNPs could account for 30% of the
genetic susceptibility for developing schizophrenia.
Research methods
Epigenetics can be studied and researched through various methods. One of the most common methods is looking at postmortem brain tissue
of patients with schizophrenia 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.
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.
Epigenetic alterations
Epigenetics
(translated as "above genetics") is the study of how genes are
regulated through reversible and heritable molecular mechanisms. The
epigenetic changes modify gene expression through either activation of
the gene that codes for a certain protein, or repression of the gene.
There are two main categories of modifications: the methylation of DNA and modifications to histones.
Research findings have demonstrated that several examples of both of
these changes are linked to schizophrenia and its symptoms.
Evidence of epigenetic regulation is still sparse, and just as genetic
culprits for the disease remain nebulous, there is no definite answer to
what epigenetic alterations should be expected in patients with
schizophrenia.
Mechanisms of epigenetics in the cell
DNA methylation
DNA methylation is the covalent addition of a methyl group to a segment of the DNA code. These -CH3 groups are added to cytosine residues by the DNMT (DNA Methytransferases) enzymes. The binding methyl group to promoter regions interferes with the binding of transcription factors and silences the gene by preventing the transcription of that code.
DNA methylation is one of the most well studied epigenetic mechanisms
and there have been several findings linking it to schizophrenia.
Differential DNA methylation has been identified in the schizophrenic epigenome across 4 different regions of the brain.
Hypermethylation of genes in neurotransmitter pathways (including GAD1,
RELN, and the serotonin pathway) as well as hypomethylation of genes in
other pathways (such as the dopaminergic pathway) have been observed in
schizophrenic patients.
A broad range of genomic methylation patterns have been observed in
patients with schizophrenia, and although a definite explanation is not
in place, there are enough consistent abnormalities to suspect that
differential methylation may play a substantial role in the pathogenesis
of schizophrenia.
Methylation of GABAergic genes
It has been consistently shown in various studies that levels of reelin and GAD67 are downregulated in the cortical and hippocampal
tissue samples of individuals with schizophrenia. These proteins are
used by GABAergic neurons, and abnormalities in their levels could
result in some of the symptoms found in individuals with schizophrenia.
The genes for these two proteins are found in areas of the genetic code
that can be methylated (see CpG island).
Recent studies have demonstrated an epigenetic link between the levels
of the proteins and schizophrenia. One study found that cortical neurons
with lower levels of GAD67 and reelin also showed increased levels of
DNMT1, one of the enzymes that adds a methyl group. It has also been
shown that a schizophrenic-type state can be induced in mice when they
were chronically given l-methionine, a precursor necessary for DNMT
activity. These and other findings provide a strong link between
epigenetic changes and schizophrenia.
Methylation of BDNF
DNA
methylation can also affect expression of BDNF (brain derived
neurotrophic factor). The BDNF protein is important for cognition,
learning, and even vulnerability to early life trauma. Sun et al. showed
that fear condition led to changes in DNA methylation levels in BDNF
promoter regions in hippocampal neurons. It was also shown that
inhibiting DNMT activity led to change in levels of BDNF in the
hippocampus. Methylation of BDNF DNA has also been shown to be affected
by post-natal social experiences, stressful environment, and social
interaction deprivation. Furthermore, these stimuli have also been
linked to increased anxiety, problems with cognition, etc. While a
direct link between schizophrenia and BDNF levels hasn't been
established, these findings suggest a relation to many problems that are
similar to symptoms.
Histone modifications
Histones
are proteins that the DNA chromosome are wrapped around. Histones are
present as an octamer (set of 8 proteins) and they can be modified
through acetylation, methylation, SUMOylation, ubiquitination, phosphorylation,
etc. These changes can either open or close up the chromosome. Thus,
depending on which histone is modified and the exact process, histone
modifications can either silence or promote gene expression (while DNA
methylation almost always silences).
Because the sub-field of histone modifications is relatively new,
there aren't many results yet. Investigations into these epigenetic
regulations indicate that therapeutic pathways targeting epigenetic
mechanisms like differential methylation and acetylation may be
beneficial.
Some studies have found that patients with schizophrenia have higher
levels of methylation at H3 (the 3rd histone in the octamer) in the
prefrontal cortex, an area that could be related to the negative
symptoms. A prominent example is the increased repressive methylation of
histone 3 (H3K9me2), which has been associated with both age of disease
onset and treatment resistance. It has also been shown that histone acetylation and phosphorylation is increased at the promoter for the BDNF protein, which is involved in learning and memory.
More recent studies have found that postmortem brain tissue from patients with schizophrenia had higher levels of HDAC,
histone deacetylase, an enzyme that remove acetyl groups from histones.
HDAC1 levels are inversely correlated with GAD67 protein expression,
which is decreased in patients with schizophrenia.
Heritable epigenetic alterations
Studies have shown that epigenetic changes can be passed on to future generations through meiosis and mitosis.
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 be true for patients with schizophrenia 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.
Another study has shown that the methylation of the BDNF gene, which
can be affected by early life stress and abuse, is also transmittable to
future generations.
In addition to epigenetic effects as a result of maternal
influence during important stages of neurodevelopment, studies show that
nutrient deprivation can result in epigenetic modifications that are
maintained from generation to generation. Historically, famines are thought to cause changes in epigenetic regulation within the human genome.
Specifically, deprivation of nutrients is thought to alter methylation
patterns in mammals, and several case studies have shown that periods of
famine are positively correlated to increased incidences of
schizophrenia in certain populations. Babies born during periods of famine were up to twice as likely to develop schizophrenia or schizophrenia spectrum disorder.
Thus, researchers believe that the development of schizophrenia is
linked to nutrient deprivation. The leading hypothesis for how this is
accomplished is via subtle epigenetic alterations following nutrient
deprivation, such as the hypermethylation of genes in neurotransmitter
pathways, since it is well documented that dietary restriction has an
effect on DNA methylation states.
This line of thinking is further supported by studies showing that
deficiencies in certain nutrients, including choline, folate and vitamin
B12 which are required for the creation S-adenosylmethionine (SAM), are also linked with increasing the epigenetic factors associated with increased risk of schizophrenia. Evidence is still mounting in this area, but the existing correlations are notably strong.
Environmental risks and causes
While
there haven't been many studies linking environmental factors to
schizophrenia-related epigenetics mechanisms at this point in the field,
a few studies 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.
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.
Methamphetamine has also been linked to schizophrenia or similar
psychotic symptoms. A recent study found that methamphetamine users had
altered DNMT1 levels, similar to how patients with schizophrenia have
shown abnormal levels of DNMT1 in GABAergic neurons.
Research has shown that there is not a 100% likelihood for
genetically inheriting schizophrenia- as in monozygotic twin pairs, when
one twin is diagnosed with schizophrenia, there is only a 50% chance
that the other twin will also be diagnosed with schizophrenia. This
finding shows that environmental influences play a role in the
development of schizophrenia.
Maternal effects
have also been shown to increase the rate of schizophrenia. It has been
hypothesized that babies born in winter and spring have higher rates of
schizophrenia than babies born in the summer and fall because of the
increase in respiratory infections during the colder months.
Furthermore, a study showed that maternal respiratory infection
increased the rate of schizophrenia "three- to sevenfold," and if the
mothers would not have gotten the respiratory infection, "14 to 21% of
schizophrenia cases would have been prevented." The relative amounts of
pro-inflammatory and anti-inflammatory compounds found in maternal serum
are associated with the onset of schizophrenia, as seen in studies in
which amounts of interleukin 6 and interleukin 10, pro- and anti-
inflammatory, respectively, were manipulated. It was reported that
increasing the amount of interleukin 10 or decreasing the amount of
interleukin 6 lessened the effects of the immune system on the fetus.
These long-lasting impacts may indicate an epigenetic effects in the
offspring, however, it remains unconfirmed. A 2018 study found that
patients with schizophrenia had hypomethylation—associated with
increased expression of a gene—of the IP6 promoter region compared to
the control subjects.
DNA methylation patterns have been linked with increased
schizophrenia risk. Specifically, the hypermethylation of the promoter
region has been reported to suppress expression of reelin
(RELN) in the frontal and prefrontal cortex. Higher DNA methylation
levels of RELN promoters has been observed in schizophrenic patients.
Several other genes, including GABAergic, dopaminergic, and
serotonergic genes, have also been found to have different methylation
in patterns in those affected by schizophrenia. Those with schizophrenia
have also been noted to have increased amounts of DNMT1, which is
involved in the regulation of methylation at CpG sites. Jaffe et al.
recently found that 2104 CpG sites were differently methylated in the
prefrontal cortex those with schizophrenia as compared to those without
schizophrenia. Most notably, the differentially methylated sites were
found in genes having to do with "embryonic development, cell fate
commitment, and nervous system differentiation" as well as the time
period between late gestation and early life.
Prenatal Maternal Stress
(PNMS) is also associated with schizophrenia and schizophrenia spectrum
disorders (SSD). Several studies have shown that increased PNMS is
linked to decreased fetal growth in males who later develop SSD. It has
also been found that PNMS leading to increased morbidity and mortality
outcomes are also associates with increased risk of SSD development in
males. PNMS, especially in early pregnancy, has also been associated to
motor deficiencies and behavioral difficulties in the pre-morbid period
before schizophrenia onset, most notably in males.
One of the most interesting findings relating an environmental
factor with schizophrenic epigenetic mechanisms is exposure to nicotine.
It has been widely reported that 80% of patients with schizophrenia use
some form of tobacco.
Furthermore, smoking appeared to increase cognition in individuals with
schizophrenia. However, it was only a recent study Satta et al.that
showed that nicotine leads to decreased levels of DNMT1 in GABAergic
mouse neurons, a molecule which adds methyl groups to DNA. This led to
increased expression of GAD67.
Research limitations
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 patient with schizophrenia. 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, patients with schizophrenia.
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.
Detection and treatment
The
advent of epigenetics as an avenue to pursue schizophrenic research has
brought about many possibilities for both early detection, diagnoses,
and treatment. While this field is still at an early stage, there have
already been promising findings. Some postmortem brain studies looking
at the gene expression of histone methylation has shown promising
results that might be used for early detection in other patients.
However, the bulk of the translational research focus and findings have
been on therapeutic interventions.
Therapeutics
Since
epigenetic changes are reversible and susceptible pharmacological
treatments and drugs, there is a great deal of promise in developing
treatments. As many have pointed out, schizophrenia is a lifelong
disorder that has widespread effects. Thus, it may not be possible to
fully reverse the disease. Although irreversible, the lives of patients
with schizophrenia can be greatly improved through treatments that
alleviate symptoms. Treatments like anti-psychotic medications for
schizophrenia are effective, but they often have serious side effects,
and medical practitioners are always looking to improve patients'
treatment outcomes. Recent studies indicate that it may be possible to
improve upon existing treatments through epigenetic means. This provides
a promising new direction for disease management. Pharmaceuticals that
directly affect epigenetic markers could be used to improve the efficacy
of a patient's current treatment or serve as an updated treatment
regiment altogether.
As previously discussed, schizophrenia is associated with
elevated levels of gene methylation and repressive histone marks,
including H3K9me2. Mood stabilizers
have become a therapeutic method of interest in treating schizophrenia
due to their ability to reverse epigenetic alterations like repressive
histone marks. Mood stabilizers that are known to target epigenetic markers associated with schizophrenia include lithium, valproate, lamotrigine, and carbamazepine.
Targeting histones modifications
HDAC
(histone deacetylase) inhibitors are one class of drugs that are being
investigated. Studies have shown that levels of reelin and GAD67 (which
are decreased in schizophrenic animal models) are both upregulated after
treatment with HDAC inhibitors. Furthermore, there is the added benefit
of selectivity, as HDAC inhibitors can be specific to cell type, tissue
type, and even regions of the brain.
Valproate, a psychotropic drug, is an HDAC inhibitor that is frequently used to treat patients with schizophrenia. Valproate leads to both increased H3 and H4 acetylation as well as increased GAD67 and reelin mRNA levels in lymphocytes.
Lithium has also been shown to be highly effective at increasing
histone acetylation and presence of GAD67 and reelin transcripts in
patients experiencing psychotic symptoms.
HMT
(histone demethylase) inhibitors also act on histones. They prevent the
demethylation of the H3K4 histone protein and open up that part of the
chromatin. Tranylcypromine, an antidepressant,
has been shown to have HMT inhibitory properties, and in a study,
treatment of patients with schizophrenia with tranylcypromine showed
improvements regarding negative symptoms.
In early studies, imipramine, an antidepressant drug, was shown to be able to remove the repressive epigenetic mark H3K9me2. Decreasing repression at this marker appears to improve treatment outcomes for patients taking antipsychotic medications.
Targeting DNA methylation
Among
long-term antipsychotic users, post-mortem tissue analysis finds that
genes that are typically methylated in patients with psychosis are
hypomethylated after lifelong antipsychotic use.
In other words, anti-psychotic drugs are able to reduce methylation of
genes in long-term users. Removing repressive epigenetic marks is only
part of how these drugs modify the epigenome of patients with psychotic
symptoms. Antipsychotics are associated with both the induction and
inhibition of DNA methylation, which can lead to the simultaneous
upregulation and downregulation of different genes in patients.
While significant variation in methylation patterns have been recorded
in patients using antipsychotic drugs, the evidence in this area is not
yet sufficient to determine the exact mechanism underlying how these
drugs influence methylation. Schizophrenia is a complex, multifaceted illness, and the variety of methylation patterns observed affirms this knowledge.
DNMT inhibitors have also been shown to increase levels of the
reeling protein and GAD67 in cell cultures. Some of the current DNMT
inhibitors, however, like zebularine and procainamide, do not cross the
blood brain barrier and would not prove as effective a treatment. While
DNMT inhibitors would prevent the addition of a methyl group, there is
also research done on DNA demethylate inducers, which would
pharmacologically induce the removal of methyl groups. Current
antipsychotic drugs, like clozapine and sulpiride, have been shown to also induce demethylation.
Behavioral epigenetics is the field of study examining the role of epigenetics in shaping animal and humanbehavior. It seeks to explain how nurture shapes nature, where nature refers to biological heredity
and nurture refers to virtually everything that occurs during the
life-span (e.g., social-experience, diet and nutrition, and exposure to
toxins). Behavioral epigenetics attempts to provide a framework for understanding how the expression of genes is influenced by experiences and the environment to produce individual differences in behaviour, cognition, personality, and mental health.
Epigenetic gene regulation involves changes other than to the sequence of DNA and includes changes to histones (proteins around which DNA is wrapped) and DNA methylation. These epigenetic changes can influence the growth of neurons in the developing brain as well as modify the activity of neurons in the adult brain. Together, these epigenetic changes in neuron structure and function can have a marked influence on an organism's behavior.
In biology, and specifically genetics, epigenetics is the study of heritable changes in gene activity which are not caused by changes in the DNA
sequence; the term can also be used to describe the study of stable,
long-term alterations in the transcriptional potential of a cell that
are not necessarily heritable.
Examples of mechanisms that produce such changes are DNA methylation and histone modification, each of which alters how genes are expressed without altering the underlying DNA sequence. Gene expression can be controlled through the action of repressor proteins that attach to silencer regions of the DNA.
DNA methylation turns a gene "off" – it results in the inability of
genetic information to be read from DNA; removing the methyl tag can
turn the gene back "on".
Histone modification changes the way that DNA is packaged into chromosomes. These changes impact how genes are expressed.
Epigenetics has a strong influence on the development of an organism and can alter the expression of individual traits. Epigenetic changes occur not only in the developing fetus, but also in individuals throughout the human life-span. Because some epigenetic modifications can be passed from one generation to the next, subsequent generations may be affected by the epigenetic changes that took place in the parents.
Discovery
The first documented example of epigenetics affecting behavior was provided by Michael Meaney and Moshe Szyf. While working at McGill University in Montréal in 2004, they discovered that the type and amount of nurturing a mother rat provides in the early weeks of the rat's infancy determines how that rat responds to stress later in life. This stress sensitivity was linked to a down-regulation in the expression of the glucocorticoid receptor in the brain. In turn, this down-regulation was found to be a consequence of the extent of methylation in the promoter region of the glucocorticoid receptor gene. Immediately after birth, Meaney and Szyf found that methyl groups repress the glucocorticoid receptor
gene in all rat pups, making the gene unable to unwind from the histone
in order to be transcribed, causing a decreased stress response.
Nurturing behaviours from the mother rat were found to stimulate
activation of stress signalling pathways that remove methyl groups from
DNA. This releases the tightly wound gene, exposing it for
transcription. The glucocorticoid gene is activated, resulting in
lowered stress response. Rat pups that receive a less nurturing
upbringing are more sensitive to stress throughout their life-span.
This pioneering work in rodents has been difficult to replicate
in humans because of a general lack of availability of human brain
tissue for measurement of epigenetic changes.
Research into epigenetics in psychology
Anxiety and risk-taking
Monozygotic twins are identical twins. Twin studies help to reveal epigenetic differences related to various aspects of psychology.
In a small clinical study in humans published in 2008, epigenetic differences were linked to differences in risk-taking and reactions to stress in monozygotic twins.
The study identified twins with different life paths, wherein one twin
displayed risk-taking behaviours, and the other displayed risk-averse
behaviours. Epigenetic differences in DNA methylation of the CpG islands proximal to the DLX1 gene correlated with the differing behavior.
The authors of the twin study noted that despite the associations
between epigenetic markers and differences personality traits,
epigenetics cannot predict complex decision-making processes like career
selection.
Animal and human studies have found correlations between poor care
during infancy and epigenetic changes that correlate with long-term
impairments that result from neglect.
Studies in rats have shown correlations between maternal care in
terms of the parental licking of offspring and epigenetic changes.
A high level of licking results in a long-term reduction in stress
response as measured behaviorally and biochemically in elements of the hypothalamic-pituitary-adrenal axis (HPA). Further, decreased DNA methylation of the glucocorticoid receptor
gene were found in offspring that experienced a high level of licking;
the glucorticoid receptor plays a key role in regulating the HPA.
The opposite is found in offspring that experienced low levels of
licking, and when pups are switched, the epigenetic changes are
reversed. This research provides evidence for an underlying epigenetic
mechanism. Further support comes from experiments with the same setup, using drugs that can increase or decrease methylation.
Finally, epigenetic variations in parental care can be passed down
from one generation to the next, from mother to female offspring. Female
offspring who received increased parental care (i.e., high licking)
became mothers who engaged in high licking and offspring who received
less licking became mothers who engaged in less licking.
In humans, a small clinical research study showed the relationship between prenatal exposure to maternal mood and genetic expression resulting in increased reactivity to stress in offspring. Three groups of infants were examined: those born to mothers medicated for depression with serotonin reuptake inhibitors;
those born to depressed mothers not being treated for depression; and
those born to non-depressed mothers. Prenatal exposure to
depressed/anxious mood was associated with increased DNA methylation at
the glucocorticoid receptor gene and to increased HPA axis stress
reactivity. The findings were independent of whether the mothers were being pharmaceutically treated for depression.
Recent research has also shown the relationship of methylation of
the maternal glucocorticoid receptor and maternal neural activity in
response to mother-infant interactions on video.
Longitudinal follow-up of those infants will be important to
understand the impact of early caregiving in this high-risk population
on child epigenetics and behavior.
A 2010 review discussed the role of DNA methylation in memory
formation and storage, but the precise mechanisms involving neuronal
function, memory, and methylation reversal remained unclear at the time.
Further research investigated the molecular basis for long-term memory. By 2015 it had become clear that long-term memory requires gene transcription activation and de novo protein synthesis.
Long-term memory formation depends on both the activation of memory
promoting genes and the inhibition of memory suppressor genes, and DNA methylation/DNA demethylation was found to be a major mechanism for achieving this dual regulation.
Rats with a new, strong long-term memory due to contextual fear conditioning have reduced expression of about 1,000 genes and increased expression of about 500 genes in the hippocampus of the brain
24 hours after training, thus exhibiting modified expression of 9.17%
of the rat hippocampal genome. Reduced gene expressions were associated
with methylations of those genes and hypomethylation was found for
genes involved in synaptic transmission and neuronal differentiation.
Further research into long-term memory has shed light on the
molecular mechanisms by which methylation is created or removed, as
reviewed in 2022. These mechanisms include, for instance, signal-responsive TOP2B-induced double-strand breaks in immediate early genes.
More than 100 DNA double-strand breaks occur, both in the hippocampus
and in the medial prefrontal cortex (mPFC), in two peaks, at 10 minutes
and at 30 minutes after contextual fear conditioning.
This appears to be earlier than the DNA methylations and
demethylations of neuron DNA in the hippocampus that were measured at
one hour and 24 hours after contextual fear conditioning.
The double strand breaks occur at known memory-related immediate early genes (among other genes) in neurons after neuron activation.[36][35] These double-strand breaks allow the genes to be transcribed and then translated into active proteins.
DNMT3A2 is another immediate early gene whose expression in neurons can be induced by sustained synaptic activity.[38]
DNMTs bind to DNA and methylate cytosines at particular locations in
the genome. If this methylation is prevented by DNMT inhibitors, then
memories do not form.
If DNMT3A2 is over-expressed in the hippocampus of young adult mice it
converts a weak learning experience into long-term memory and also
enhances fear memory formation.
In another mechanism reviewed in 2022, the messenger RNAs of many genes that had been subjected to methylation-controlled increases or decreases are transported by neural granules (messenger RNPs) to the dendritic spines. At these locations the messenger RNAs can be translated into the proteins that control signaling at neuronalsynapses.
Studies in rodents have found that the environment exerts an influence on epigenetic changes related to cognition, in terms of learning and memory; environmental enrichment correlated with increased histone acetylation, and verification by administering histone deacetylase inhibitors
induced sprouting of dendrites, an increased number of synapses, and
reinstated learning behaviour and access to long-term memories.
Research has also linked learning and long-term memory formation to
reversible epigenetic changes in the hippocampus and cortex in animals
with normal-functioning, non-damaged brains. In human studies, post-mortem brains from Alzheimer's patients show increased histone de-acetylase levels.
This diagram depicts the signaling events in the brain's reward center that are induced by chronic high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, like amphetamine, methamphetamine, and phenethylamine. Following presynaptic dopamine and glutamateco-release by such psychostimulants, postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP-dependent pathway and a calcium-dependent pathway that ultimately result in increased CREB phosphorylation. Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors; c-Fosrepression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron. A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for 1–2 months, slowly accumulates following repeated high-dose exposure to stimulants through this process. ΔFosB functions as "one of the master control proteins" that produces addiction-related structural changes in the brain, and upon sufficient accumulation, with the help of its downstream targets (e.g., nuclear factor kappa B), it induces an addictive state.
Environmental and epigenetic influences seem to work together to increase the risk of addiction. For example, environmental stress has been shown to increase the risk of substance abuse. In an attempt to cope with stress, alcohol and drugs can be used as an escape.
Once substance abuse commences, however, epigenetic alterations may
further exacerbate the biological and behavioural changes associated
with addiction.
Even short-term substance abuse can produce long-lasting epigenetic changes in the brain of rodents, via DNA methylation and histone modification. Epigenetic modifications have been observed in studies on rodents involving ethanol, nicotine, cocaine, amphetamine, methamphetamine and opiates.
Specifically, these epigenetic changes modify gene expression, which in
turn increases the vulnerability of an individual to engage in repeated
substance overdose in the future. In turn, increased substance abuse
results in even greater epigenetic changes in various components of a
rodent's reward system (e.g., in the nucleus accumbens). Hence, a cycle emerges whereby changes in areas of the reward system
contribute to the long-lasting neural and behavioural changes
associated with the increased likelihood of addiction, the maintenance
of addiction and relapse.
In humans, alcohol consumption has been shown to produce epigenetic
changes that contribute to the increased craving of alcohol. As such,
epigenetic modifications may play a part in the progression from the
controlled intake to the loss of control of alcohol consumption.
These alterations may be long-term, as is evidenced in smokers who
still possess nicotine-related epigenetic changes ten years after cessation. Therefore, epigenetic modifications
may account for some of the behavioural changes generally associated
with addiction. These include: repetitive habits that increase the risk
of disease, and personal and social problems; need for immediate gratification; high rates of relapse following treatment; and, the feeling of loss of control.
Evidence for relevant epigenetic changes came from human studies involving alcohol,
nicotine, and opiate abuse. Evidence for epigenetic changes stemming
from amphetamine and cocaine abuse derives from animal studies. In
animals, drug-related epigenetic changes in fathers have also been shown
to negatively affect offspring in terms of poorer spatial working memory, decreased attention and decreased cerebral volume.
Epigenetic changes may help to facilitate the development and maintenance of eating disorders via influences in the early environment and throughout the life-span. Pre-natal
epigenetic changes due to maternal stress, behaviour and diet may later
predispose offspring to persistent, increased anxiety and anxiety disorders. These anxiety issues can precipitate the onset of eating disorders and obesity, and persist even after recovery from the eating disorders.
Epigenetic differences accumulating over the life-span may
account for the incongruent differences in eating disorders observed in
monozygotic twins. At puberty, sex hormones
may exert epigenetic changes (via DNA methylation) on gene expression,
thus accounting for higher rates of eating disorders in men as compared
to women. Overall, epigenetics contribute to persistent, unregulated self-control behaviours related to the urge to binge.
Epigenetic changes including hypomethylation of glutamatergic genes (i.e., NMDA-receptor-subunit gene NR3B and the promoter of the AMPA-receptor-subunit gene GRIA2) in the post-mortem brains of people with schizophrenia are associated with increased levels of the neurotransmitter glutamate. Since glutamate is the most prevalent, fast, excitatory neurotransmitter, increased levels may result in the psychotic episodes related to schizophrenia.
Epigenetic changes affecting a greater number of genes have been
detected in men with schizophrenia as compared to women with the
illness.
Population studies have established a strong association linking schizophrenia in children born to older fathers. Specifically, children born to fathers over the age of 35 years are up to three times more likely to develop schizophrenia. Epigenetic dysfunction in human male sperm cells,
affecting numerous genes, have been shown to increase with age. This
provides a possible explanation for increased rates of the disease in
men. To this end, toxins (e.g., air pollutants) have been shown to increase epigenetic differentiation. Animals exposed to ambient air from steel mills and highways show drastic epigenetic changes that persist after removal from the exposure. Therefore, similar epigenetic changes in older human fathers are likely. Schizophrenia studies provide evidence that the nature versus nurture debate in the field of psychopathology
should be re-evaluated to accommodate the concept that genes and the
environment work in tandem. As such, many other environmental factors
(e.g., nutritional deficiencies and cannabis use) have been proposed to increase the susceptibility of psychotic disorders like schizophrenia via epigenetics.
Bipolar disorder
Evidence for epigenetic modifications for bipolar disorder is unclear. One study found hypomethylation of a gene promoter of a prefrontal lobe enzyme (i.e., membrane-bound catechol-O-methyl transferase, or COMT) in post-mortem brain samples from individuals with bipolar disorder. COMT is an enzyme that metabolizesdopamine in the synapse. These findings suggest that the hypomethylation of the promoter
results in over-expression of the enzyme. In turn, this results in
increased degradation of dopamine levels in the brain. These findings
provide evidence that epigenetic modification in the prefrontal lobe is a
risk factor for bipolar disorder. However, a second study found no epigenetic differences in post-mortem brains from bipolar individuals.
Major depressive disorder
The causes of major depressive disorder (MDD) are poorly understood from a neuroscience perspective.
The epigenetic changes leading to changes in glucocorticoid receptor
expression and its effect on the HPA stress system discussed above, have
also been applied to attempts to understand MDD.
Much of the work in animal models has focused on the indirect downregulation of brain derived neurotrophic factor (BDNF) by over-activation of the stress axis. Studies in various rodent models of depression, often involving
induction of stress, have found direct epigenetic modulation of BDNF as
well.
Psychopathy
Epigenetics may be relevant to aspects of psychopathic behaviour through methylation and histone modification. These processes are heritable but can also be influenced by environmental factors such as smoking and abuse. Epigenetics may be one of the mechanisms through which the environment can impact the expression of the genome. Studies have also linked methylation of genes associated with nicotine and alcohol dependence in women, ADHD, and drug abuse.
It is probable that epigenetic regulation as well as methylation
profiling will play an increasingly important role in the study of the
play between the environment and genetics of psychopaths.
Social insects
Several
studies have indicated DNA cytosine methylation linked to the social
behavior of insects, such as honeybees and ants. In honeybees, when
nurse bee switched from her in-hive tasks to out foraging, cytosine
methylation marks are changing. When a forager bee was reversed to do
nurse duties, the cytosine methylation marks were also reversed. Knocking down the DNMT3 in the larvae changed the worker to queen-like phenotype.
Queen and worker are two distinguish castes with different morphology,
behavior, and physiology. Studies in DNMT3 silencing also indicated DNA
methylation may regulate gene alternative splicing and pre-mRNA
maturation.
Limitations and future direction
Many researchers contribute information to the Human Epigenome Consortium. The aim of future research is to reprogram epigenetic changes to help with addiction, mental illness, age related changes, memory decline, and other issues. However, the sheer volume of consortium-based data makes analysis difficult. Most studies also focus on one gene.
In actuality, many genes and interactions between them likely
contribute to individual differences in personality, behaviour and
health.
As social scientists often work with many variables, determining the
number of affected genes also poses methodological challenges. More
collaboration between medical researchers, geneticists and social
scientists has been advocated to increase knowledge in this field of
study.
Limited access to human brain tissue poses a challenge to conducting human research.
Not yet knowing if epigenetic changes in the blood and (non-brain)
tissues parallel modifications in the brain, places even greater
reliance on brain research. Although some epigenetic studies have translated findings from animals to humans, a some researchers caution about the extrapolation of animal studies to humans.
One view notes that when animal studies do not consider how the
subcellular and cellular components, organs and the entire individual
interact with the influences of the environment, results are too
reductive to explain behaviour.
Some researchers note that epigenetic perspectives will likely be incorporated into pharmacological treatments.
Others caution that more research is necessary as drugs are known to
modify the activity of multiple genes and may, therefore, cause serious
side effects.
However, the ultimate goal is to find patterns of epigenetic changes
that can be targeted to treat mental illness, and reverse the effects of
childhood stressors, for example. If such treatable patterns eventually
become well-established, the inability to access brains in living
humans to identify them poses an obstacle to pharmacological treatment. Future research may also focus on epigenetic changes that mediate the impact of psychotherapy on personality and behaviour.
Most epigenetic research is correlational; it merely establishes
associations. More experimental research is necessary to help establish
causation. Lack of resources has also limited the number of intergenerational studies. Therefore, advancing longitudinal
and multigenerational, experience-dependent studies will be critical to
further understanding the role of epigenetics in psychology.
