Epigenetics of schizophrenia
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.
[3] 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.
[6][7] 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.
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.
[8] Most maternal effects involved in schizophrenia development have to do with immune system activation and associated cytokine and neurogenesis mechanisms rather than genetic changes.
[9] 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.
[10] There are various environmental factors that have been suggested, including the use of marijuana, complications during pregnancy, socioeconomic status and environment, and maternal malnutrition.
[13][11] 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.
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.
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.
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.
Sun et al. showed that fear condition led to changes in DNA methylation levels in BDNF promoter regions in hippocampal neurons.
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.
[13] 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.
[16] These findings suggest that environmental factors that the parents face can possibly affect how the child's genetic code is regulated.
[1] 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.
[13] 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.
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.
Specifically, the hypermethylation of the promoter region has been reported to suppress expression of reelin (RELN) in the frontal and prefrontal cortex.
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.
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.
[15] The advent of epigenetics as an avenue to pursue schizophrenic research has brought about many possibilities for both early detection, diagnoses, and treatment.
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.
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.
[30] Mood stabilizers that are known to target epigenetic markers associated with schizophrenia include lithium, valproate, lamotrigine, and carbamazepine.
Studies have shown that levels of reelin and GAD67 (which are decreased in schizophrenic animal models) are both upregulated after treatment with HDAC inhibitors.
[30] 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.
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.
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.
