Behaviors and Anatomy

Role of miRNA in psychiatric disorders

By March 23, 2018 No Comments

Causes of Psychiatric Disorders

Psychiatric disorders have become one of the great concerns today. They are caused by a combined influence of gene and environment interaction. Genes influence a person’s vulnerability to diseases. What mostly influences whether a person will suffer from a psychiatric disorder is their environment, predominantly their lifestyle and level of stress. The mechanisms that enable the environment to have an effect on gene expression are called epigenetic mechanisms. They affect levels of gene expression, not by changing DNA, but through other processes, such as histone modification, DNA methylation and post-translational regulation by microRNA.

miRNA

MicroRNA (miRNA) have only been discovered in recent years. miRNA is an approximately 22 nucleotide non-coding RNA, whose functions are post-transcriptional regulation of gene expression and RNA silencing. These molecules can be found both inside the cell and in the extracellular space. It is estimated that there are around one thousand miRNAs and that they regulate expression of more than a half protein coding genes. miRNAs act as a fine tuner of expression level of genes, and it is speculated that they can influence the behavior of neuronal populations and neuronal networks. Having this in mind, lately, there have been suggestions that miRNAs potentially have a role in human and animal behavior.
Although there are not many studies that have explored the relationship between miRNA and behavior, this hypothesis offers a new possibility for diagnosing psychiatric diseases and for creating new ways of treatment.

What We Known so Far

Postmortem studies from patients who suffered from psychiatric disorders show that these patients had similar miRNA expression profiles. This finding indicates that there might be a characteristic miRNA expression pattern in patients suffering from specific psychiatric diseases, and thus, that miRNA somehow contribute to these disorders [1].

It has been shown in animal models of psychiatric disorders that specific miRNAs take part in the development of the disorder. In a study in mice, it was shown that offspring of stressed parent exhibited altered behaviors and different epigenetic modifications in certain brain regions, although the offspring was not experiencing any kind of stress [2]. In this study, the male mice were stressed for a period of time, and then were let to mate with a female. After delivering the litter, the offspring was taken and divided into three groups –controls, male parent stressed in puberty and male parent stressed in adulthood. Then the offspring was tested for their Hypothalamus-pituitary-adrenal (HPA) axis responsivity by measuring corticosterone levels. Other tests included performance on tail suspension test (TST), Barnes maze and in the light-dark box. This study found that the HPA axis in the offspring of stressed fathers was dysregulated. miRNA in the sperm of the fathers, stressed both in puberty and adulthood, influenced the genes responsible for regulation of HPA axis, and therefore, the levels of corticosterone in the offspring when exposed to a stressful situation. TST showed no effect of paternal stress on total time spent immobile. Analysis of latency to find the target on the Barnes Maze similarly revealed no effect of paternal stress and latency to find target was decreasing across trials for all three groups of the offspring. In the light-dark box, there was also no effect of paternal stress both on the time spent in the light compartment or the number of transitions made from one box to the other.

One study showed that inserting sperm miRNA of stressed male mice into the oocyte produced by healthy non-stressed parents, introduced altered stress like behavior in the offspring. This study indicates that miRNA expression is genetically inherited [3].

Different studies have identified miRNAs and their involvement in several psychiatric disorders.

Kocerha et al. found that miRNA 219 promotes schizophrenia-like behaviors [4].

miRNA 1202 is found to be a predictor of response to antidepressants [1].

miRNA in psychiatric disorders

Another study [5] compared the behavior of miRNA 135 knockdown mice and controls. In the light-dark transfer test, knockdown mice showed increased anxiety-like behavior than the controls. The mice also walked less and spent less time in the light compartment of the box. Similar behavior was exhibited in the elevated plus maze test and open arms maze test. This study showed that miRNA 135 has an anxiety-reducing effect.

One study showed that miRNA 34 inhibits stress-induced anxiety [6]. Haramati et al. used mice strain with overexpressed miRNA 34. These mice showed to be unaffected by acute stress compared to controls. Even after 24 hours of acute stress, mice with overexpressed miRNA 34 visited the light compartment in the light-dark box more, traveled longer distances and had shorter latency to enter the light department of the box, compared to the controls. The mice were stressed even further and afterward, were tested in the elevated plus maze. The results showed that the miRNA 34 overexpression mice spent more time and traveled larger distances in the open arm of the maze than the controls. This study clearly shows the anxiolytic effects of miRNA 34 overexpression. Other studies show that miRNAs play a role in addictive behaviors and learning [7,8,9].

Study of Issler et al. [5] showed that miRNAs can act as biomarkers for major depression disorder (MDD). This study also showed that this miRNA from blood can be used to identify which patients respond to antidepressants such as SSRI. This finding was supported by postmortem studies that have identified that miR-1202 was downregulated in brain tissue of patients with MDD [1].

Conclusion

Different levels of miRNA expression are related to different kinds of behavior. The exact mechanisms through which miRNA modulate behavior are still not fully understood. What is known is that expression levels of some miRNAs was changed after administration of certain drugs and after some environmental changes. This change in miRNA expression levels leads to a change in expression of genes, which in turn affect certain behavioral patterns. Therefore, studying the role of miRNA in psychiatric disorders can help understand the mechanisms that underlie certain psychiatric disorders and hence, help develop new means of diagnosis and therapy.

References

  1. Lopez, J. P. et al. (2014). miR 1202 is a primate-specific and brain-enriched microRNA involved in major depression and antidepressant treatment. Nature Medicine. 20, 764–768.
  2. Rodgers, A. B., Morgan, C. P., Bronson, S. L., Revello, S. & Bale, T. L.(2013). Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation. J. Neurosci. 33, 9003–9012.
  3. Gapp, K. et al. (2014).Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nature Neurosci. 17, 667–669.
  4. Kocerha, J. et al. (2009).MicroRNA 219 modulates NMDA receptor-mediated neurobehavioral dysfunction. Proc. Natl Acad. Sci. USA 106, 3507–3512.
  5. Issler, O. et al.(2014).MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity. Neuron 83, 344–360.
  6. Haramati, S. et al. (2011). MicroRNA as repressors of stress-induced anxiety: the case of amygdalar miR 34. Journal of Neuroscience. 31, 14191–14203.
  7. Chandrasekar, V. & Dreyer, J. L. (2009). microRNAs miR 124, let 7d and miR 181a regulate cocaine-induced plasticity. Mol. Cell Neurosci. 42, 350–362.
  8. Chandrasekar, V. & Dreyer, J. L. (2011). Regulation of miR 124, let 7d, and miR 181a in the accumbens affects the expression, extinction, and reinstatement of cocaine-induced conditioned place preference. Neuropsychopharmacology36, 1149–1164.
  9. Gao, J. et al. (2010).A novel pathway regulates memory and plasticity via SIRT1 and miR 134. Nature 466, 1105–1109.

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