Review
Evidence demonstrating role of microRNAs in the etiopathology of major depression

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Abstract

Major depression is a debilitating disease. Despite a tremendous amount of research, the molecular mechanisms associated with the etiopathology of major depression are not clearly understood. Several lines of evidence indicate that depression is associated with altered neuronal and structural plasticity and neurogenesis. MicroRNAs are a newly discovered prominent class of gene expression regulators that have critical roles in neural development, are needed for survival and optimal health of postmitotic neurons, and regulate synaptic functions, particularly by regulating protein synthesis in dendritic spines. In addition, microRNAs (miRNAs) regulate both embryonic and adult neurogenesis. Given that miRNAs are involved in neural plasticity and neurogenesis, the concept that miRNAs may play an important role in psychiatric illnesses, including major depression, is rapidly advancing. Emerging evidence demonstrates that the expression of miRNAs is altered during stress, in the brain of behaviorally depressed animals, and in human postmortem brain of depressed subjects. In this review article, the possibility that dysregulation of miRNAs and/or altered miRNA response may contribute to the etiology and pathophysiology of depressive disorder is discussed.

Highlights

ā–ŗ MicroRNAs (miRNAs) are small noncoding RNAs that regulate the expression of several genes. ā–ŗ Recent evidence points toward a role of miRNAs in synaptic plasticity and neurogenesis, phenomena believed to be associated with stress-related disorders, including major depression. ā–ŗ A direct role of miRNAs in the etiology of depression is emerging as the expression of miRNAs is altered in the brain of stressed and behaviorally depressed animals as well as in depressed patients. ā–ŗ This review article aims to describe the recent evidence that demonstrates that miRNAs may play a critical role in the etiology of major depression.

Introduction

Depression is a major public health concern. The lifetime prevalence rate of depression is approximately 5ā€“19% (Kessler et al., 1994); of those, 50ā€“85% experience multiple episodes. Depression is a major symptom of suicidal behavior (Mann, 1998, Soloff et al., 2000). Despite many years of research, the molecular and cellular mechanisms associated with depression are not clear.

Overwhelming evidence points to altered synaptic and structural plasticity and neurogenesis in major depression. In fact, major depression may result from an inability of the brain to make appropriate adaptive responses to environmental stimuli because of impaired synaptic plasticity (Manji et al., 1998, Duman et al., 2000, Duman, 2002, Fossati et al., 2004). Support for this comes from a variety of studies in depressed subjects, demonstrating compromised structural and functional plasticity (Ongur et al., 1998, Rosoklija et al., 2000, Rajkowska, 2000, Cotter et al., 2001, Miguel-Hidalgo and Rajkowska, 2002, Rajkowska and Miguel-Hidalgo, 2007); changes in synaptic circuitry (Aganova and Uranova, 1992); decreased dorsolateral prefrontal cortical activity (Dolan et al., 1993, Drevets et al., 1998); impaired synaptic connectivity between the frontal lobe and other brain regions (Andreasen, 1997, Honer, 1999); changes in the number and shape of dendritic spines, the primary location of synapse formation (Toni et al., 1999, Hajsza et al., 2005); altered dendritic morphological features of neurons in the hippocampus; decreased length and number of apical dendrites (McEwen, 2000); neuronal atrophy and decreased volume of the hippocampus (Sheline, 2000, Sala et al., 2004, Frodl et al., 2006); decreased number of neurons and glia in cortical areas (Miguel-Hidalgo and Rajkowska, 2002); and spatial cognition deficits (Sackeim, 2001). In addition, major depression is associated with a negative impact on learning and memory (Horan et al., 1997, Bearden et al., 2006); and stress, a major factor in depression, hinders performances on hippocampal-dependent memory tasks and impairs induction of hippocampal long-term potentiation (Howland and Wang, 2008). These studies clearly demonstrate impaired structural and functional plasticity in major depression; however, the precise molecular and cellular nature of events that lead to such altered plasticity, which contributes to depressive behavior, remains unclear.

Section snippets

Altered intracellular signaling and gene expression in major depression

Adaptive responses in intracellular molecules and gene expression, together with the modulation of functional responses mediated by the phosphorylation of critical proteins participate in a major way in neural plasticity. In fact, it has repeatedly been demonstrated that major depression is associated with alterations in the expression of genes that are crucial in the maintenance of neural and structural plasticity. For example, several studies have reported decreased expression of

General aspect

In the past few years, it has become clear that gene expression in the brain is regulated at many levels. In addition to the traditional transcriptional mechanisms (e.g., activation of genes by transcription factors and alternative splicing), gene expression is regulated by a variety of noncoding RNA transcripts that generate microRNAs (miRNAs), antisense RNAs, and other small RNAs that are linked to several posttranscriptional, transcriptional, and epigenetic mechanisms. Of these, the best

microRNAs and neurogenesis

Numerous studies suggest that neurogenesis is involved in learning. For example, neurogenesis in the subventricular zone is important for olfactory learning (Alonso et al., 2006), whereas hippocampal neurogenesis is involved in memory and spatial learning (Dupret et al., 2008). Enriched environment, exercise, and antidepressant treatment all increase hippocampal neurogenesis (reviewed in Lazarov et al., 2010). In contrast, stress and major depression cause decreased hippocampal neurogenesis

microRNAs and glucocorticoid receptors

Several clinical and epidemiological studies have identified stressors as important risk factors in depression (reviewed in Liu and Alloy, 2010). An overactive HPA axis is well established in stress and abnormal HPA axis in depression is one of the most consistent findings in biological psychiatry (reviewed in Wasserman et al., 2010). Most patients with depression have increased concentrations of cortisol in plasma and cerebrospinal fluid, an increased cortisol response to adrenocorticotropic

Other microRNA targets relevant to affective illnesses

An excellent review on the aspect of miRNA regulation of serotonergic transmission has recently been published (Millan, 2011). As mentioned earlier, fluoxetine regulates expression of miR-16, which acts as a negative regulator of serotonin transporter by binding to the 3ā€²-UTR region of serotonin transporter mRNA (Baudry et al., 2010). miR-15 and miR-16 repress translational of Bcl-2 (Cimmino et al., 2005), an anti-apototic protein, which has been shown to play a role in affective illnesses and

Conclusion and future studies

From the evidence discussed in this review article, it appears that miRNAs play pivotal roles in many biological phenomena, including synaptic plasticity, neurogenesis, and stress responses. All of these have been shown to participate in affective illnesses. Studies in animal models of depression and in human postmortem brain are rapidly evolving, providing direct evidence that expression levels of miRNAs are altered in depressed and bipolar patients. In addition, psychoactive drugs modify the

Conflict of interest statement

The author declares that there are no conflicts of interest.

Ethical statement

The human postmortem brain studies were approved by the Institutional Review Board of the University of Illinois at Chicago. All animals were treated and used according to the guidelines of the University of Illinois at Chicago Animal Care Committee, which parallel those of the NIH for the care and use of animals in scientific experimentation.

Acknowledgements

This research was supported by grants from National Institute of Mental Health (R01MH082802; R21MH081099; R21MH091509) and standard Research Grant from the American Foundation for Suicide Prevention to Dr. Y. Dwivedi. The author acknowledges Dr. Neil Smalheiser for collaborative studies of miRNAs in depression and learned helpless behavior.

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