SNORA69 is up-regulated in the lateral habenula of individuals with major depressive disorder.

Major depressive disorder (MDD) is a complex and potentially debilitating illness whose etiology and pathology remains unclear. Non-coding RNAs have been implicated in MDD, where they display differential expression in the brain and the periphery. In this study, we quantified small nucleolar RNA (snoRNA) expression by small RNA sequencing in the lateral habenula (LHb) of individuals with MDD (n = 15) and psychiatrically-healthy controls (n = 15). We uncovered five snoRNAs that exhibited differential expression between MDD and controls (FDR < 0.01). Specifically, SNORA69 showed increased expression in MDD and was technically validated via RT-qPCR. We further investigated the expression of Snora69 in the LHb and peripheral blood of an unpredicted chronic mild stress (UCMS) mouse model of depression. Snora69 was specifically up-regulated in mice that underwent the UCMS paradigm. SNORA69 is known to guide pseudouridylation onto 5.8S and 18S rRNAs. We quantified the relative abundance of pseudouridines on 5.8S and 18S rRNA in human post-mortem LHb samples and found increased abundance of pseudouridines in the MDD group. Overall, our findings indicate the importance of brain snoRNAs in the pathology of MDD. Future studies characterizing SNORA69's role in MDD pathology is warranted.

SNORD90 induces glutamatergic signaling following treatment with monoaminergic antidepressants.

Pharmacotherapies for the treatment of major depressive disorder were serendipitously discovered almost seven decades ago. From this discovery, scientists pinpointed the monoaminergic system as the primary target associated with symptom alleviation. As a result, most antidepressants have been engineered to act on the monoaminergic system more selectively, primarily on serotonin, in an effort to increase treatment response and reduce unfavorable side effects. However, slow and inconsistent clinical responses continue to be observed with these available treatments. Recent findings point to the glutamatergic system as a target for rapid acting antidepressants. Investigating different cohorts of depressed individuals treated with serotonergic and other monoaminergic antidepressants, we found that the expression of a small nucleolar RNA, SNORD90, was elevated following treatment response. When we increased Snord90 levels in the mouse anterior cingulate cortex (ACC), a brain region regulating mood responses, we observed antidepressive-like behaviors. We identified neuregulin 3 (NRG3) as one of the targets of SNORD90, which we show is regulated through the accumulation of N6-methyladenosine modifications leading to YTHDF2-mediated RNA decay. We further demonstrate that a decrease in NRG3 expression resulted in increased glutamatergic release in the mouse ACC. These findings support a molecular link between monoaminergic antidepressant treatment and glutamatergic neurotransmission.

Analysis on in vitro effect of lithium on telomere length in lymphoblastoid cell lines from bipolar disorder patients with different clinical response to long-term lithium treatment.

BACKGROUND: It has been suggested that bipolar disorder (BD) is associated with clinical and biological features of accelerated aging. In our previous studies, we showed that long-term lithium treatment was correlated with longer leukocyte telomere length (LTL) in BD patients. A recent study explored the role of TL in BD using patients-derived lymphoblastoid cell lines (LCLs), showing that baseline TL was shorter in BD compared to controls and that lithium in vitro increased TL but only in BD. Here, we used the same cell system (LCLs) to explore if a 7-day treatment protocol with lithium chloride (LiCl) 1 mM was able to highlight differences in TL between BD patients clinically responders (Li-R; n = 15) or non-responders (Li-NR; n = 15) to lithium, and if BD differed from non-psychiatric controls (HC; n = 15). RESULTS: There was no difference in TL between BD patients and HC. Moreover, LiCl did not influence TL in the overall sample, and there was no difference between diagnostic or clinical response groups. Likewise, LiCl did not affect TL in neural precursor cells from healthy donors. CONCLUSIONS: Our findings suggest that a 7-day lithium treatment protocol and the use of LCLs might not represent a suitable approach to deepen our understanding on the role of altered telomere dynamics in BD as previously suggested by studies in vivo.

A bidirectional competitive interaction between circHomer1 and Homer1b within the orbitofrontal cortex regulates reversal learning.

Although circular RNAs (circRNAs) are enriched in the brain, their relevance for brain function and psychiatric disorders is poorly understood. Here, we show that circHomer1 is inversely associated with relative HOMER1B mRNA isoform levels in both the orbitofrontal cortex (OFC) and stem-cell-derived neuronal cultures of subjects with psychiatric disorders. We further demonstrate that in vivo circHomer1 knockdown (KD) within the OFC can inhibit the synaptic expression of Homer1b mRNA. Furthermore, we show that circHomer1 directly binds to Homer1b mRNA and that Homer1b-specific KD increases synaptic circHomer1 levels and improves OFC-mediated behavioral flexibility. Importantly, double circHomer1 and Homer1b in vivo co-KD results in a complete rescue in circHomer1-associated alterations in both chance reversal learning and synaptic gene expression. Lastly, we uncover an RNA-binding protein that can directly bind to circHomer1 and promote its biogenesis. Taken together, our data provide mechanistic insights into the importance of circRNAs in brain function and disease.

Circular RNA circCCNT2 is upregulated in the anterior cingulate cortex of individuals with bipolar disorder.

Gene expression dysregulation in the brain has been associated with bipolar disorder, but little is known about the role of non-coding RNAs. Circular RNAs are a novel class of long noncoding RNAs that have recently been shown to be important in brain development and function. However, their potential role in psychiatric disorders, including bipolar disorder, has not been well investigated. In this study, we profiled circular RNAs in the brain tissue of individuals with bipolar disorder. Total RNA sequencing was initially performed in samples from the anterior cingulate cortex of a cohort comprised of individuals with bipolar disorder (N = 13) and neurotypical controls (N = 13) and circular RNAs were identified and analyzed using "circtools". Significant circular RNAs were validated by RT-qPCR and replicated in the anterior cingulate cortex in an independent cohort (24 bipolar disorder cases and 27 controls). In addition, we conducted in vitro studies using B-lymphoblastoid cells collected from bipolar cases (N = 19) and healthy controls (N = 12) to investigate how circular RNAs respond following lithium treatment. In the discovery RNA sequencing analysis, 26 circular RNAs were significantly differentially expressed between bipolar disorder cases and controls (FDR < 0.1). Of these, circCCNT2 was RT-qPCR validated showing significant upregulation in bipolar disorder (p = 0.03). This upregulation in bipolar disorder was replicated in an independent post-mortem human anterior cingulate cortex cohort and in B-lymphoblastoid cell culture. Furthermore, circCCNT2 expression was reduced in response to lithium treatment in vitro. Together, our study is the first to associate circCCNT2 to bipolar disorder and lithium treatment.

Treatment-emergent and trajectory-based peripheral gene expression markers of antidepressant response.

Identifying biomarkers of antidepressant response may advance personalized treatment of major depressive disorder (MDD). We aimed to identify longitudinal changes in gene expression associated with response to antidepressants in a sample of MDD patients treated with escitalopram. Patients (N = 153) from the CAN-BIND-1 cohort were treated for 8 weeks, and depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale at 0, 2, 4, 6, and 8 weeks. We identified three groups of patients according to response status: early responders (22.9%), later responders (32.0%), and nonresponders (45.1%). RNA sequencing was performed in blood obtained at weeks 0, 2, and 8. RNA expression was modeled using growth models, and differences in the longitudinal changes in expression according to response were investigated using multiple regression models. The expression of RNAs related to response was investigated in the brains of depressed individuals, as well as in neuronal cells in vitro. We identified four RNAs (CERCAM, DARS-AS1, FAM228B, HBEGF) whose change over time was independently associated with a response status. For all except HBEGF, responders showed higher expression over time, compared to nonresponders. While the change in all RNAs differentiated early responders from nonresponders, changes in DARS-AS1 and HBEGF also differentiated later responders from nonresponders. Additionally, HBEGF was downregulated in the brains of depressed individuals, and increased in response to escitalopram treatment in vitro. In conclusion, using longitudinal assessments of gene expression, we provide insights into biological processes involved in the intermediate stages of escitalopram response, highlighting several genes with potential utility as biomarkers of antidepressant response.

miR-323a regulates ERBB4 and is involved in depression.

Major depressive disorder (MDD) is a complex and debilitating illness whose etiology remains unclear. Small RNA molecules, such as micro RNAs (miRNAs) have been implicated in MDD, where they display differential expression in the brain and the periphery. In this study, we quantified miRNA expression by small RNA sequencing in the anterior cingulate cortex and habenula of individuals with MDD and psychiatrically-healthy controls. Thirty-two miRNAs showed significantly correlated expression between the two regions (False Discovery Rate < 0.05), of which four, miR-204-5p, miR-320b, miR-323a-3p, and miR-331-3p, displayed upregulated expression in MDD. We assessed the expression of predicted target genes of differentially expressed miRNAs in the brain, and found that the expression of erb-b2 receptor tyrosine kinase 4 (ERBB4), a gene encoding a neuregulin receptor, was downregulated in both regions, and was influenced by miR-323a-3p in vitro. Finally, we assessed the effects of manipulating miRNA expression in the mouse ACC on anxiety- and depressive-like behaviors. Mice in which miR-323-3p was overexpressed or knocked-down displayed increased and decreased emotionality, respectively. Additionally, these mice displayed significantly downregulated and upregulated expression of Erbb4, respectively. Overall, our findings indicate the importance of brain miRNAs in the pathology of MDD, and emphasize the involvement of miR-323a-3p and ERBB4 in this phenotype. Future studies further characterizing miR-323a-3p and neuregulin signaling in depression are warranted.

GPR56/ADGRG1 is associated with response to antidepressant treatment.

It remains unclear why many patients with depression do not respond to antidepressant treatment. In three cohorts of individuals with depression and treated with serotonin-norepinephrine reuptake inhibitor (N = 424) we show that responders, but not non-responders, display an increase of GPR56 mRNA in the blood. In a small group of subjects we also show that GPR56 is downregulated in the PFC of individuals with depression that died by suicide. In mice, we show that chronic stress-induced Gpr56 downregulation in the blood and prefrontal cortex (PFC), which is accompanied by depression-like behavior, and can be reversed by antidepressant treatment. Gpr56 knockdown in mouse PFC is associated with depressive-like behaviors, executive dysfunction and poor response to antidepressant treatment. GPR56 peptide agonists have antidepressant-like effects and upregulated AKT/GSK3/EIF4 pathways. Our findings uncover a potential role of GPR56 in antidepressant response.

Using Epigenetic Tools to Investigate Antidepressant Response.

Major depressive disorder is a chronic and debilitating illness. It is most commonly treated with antidepressant drugs, however, as the majority of patients do not respond on their first trial or following several adequate trials, there is great interest in identifying biological factors that may help select the most appropriate treatment for each patient and in understanding biological processes that mediate treatment response. Epigenetic factors, such as non-coding RNAs (ncRNAs), hold potential as biomarkers of antidepressant response. In this chapter, we review key methodological considerations when investigating ncRNA biomarkers, including biological samples and technologies which have been used in these studies. Secondly, we summarize findings from studies investigating ncRNAs in antidepressant treatment response. Finally, we discuss some of the future directions which will be necessary for the development of clinically relevant epigenetic tools.

Transcriptomic and epigenomic biomarkers of antidepressant response.

BACKGROUND: Antidepressant treatment is associated with a high rate of poor response, and thus, biomarker development is warranted. METHODS: We aimed to synthesize studies investigating gene expression, small RNAs, and epigenomic biomarkers of antidepressant response. We conducted a narrative review of the literature. RESULTS: Firstly, we detailed the challenges involved, in terms of biological tissues, relevant study time frames, and mandatory statistical tools. Secondly we synthesized results obtained in gene expression studies, focusing mainly on genome-wide studies, particularly small non-coding RNA, including micro-RNA and other small RNA species. In addition, we reviewed the potential biomarkers of antidepressant response arising from studies investigating DNA methylation variation and histone modifications. LIMITATIONS: We did not conduct a meta-analysis due to the heterogeneity of the study. CONCLUSION: Although promising, the field of gene expression and epigenomic biomarkers of antidepressant response is still in its infancy, and needs further development to define useful biomarkers in clinical practice.

MicroRNAs 146a/b-5 and 425-3p and 24-3p are markers of antidepressant response and regulate MAPK/Wnt-system genes.

Antidepressants (ADs) are the most common treatment for major depressive disorder (MDD). However, only ∼30% of patients experience adequate response after a single AD trial, and this variability remains poorly understood. Here, we investigated microRNAs (miRNAs) as biomarkers of AD response using small RNA-sequencing in paired samples from MDD patients enrolled in a large, randomized placebo-controlled trial of duloxetine collected before and 8 weeks after treatment. Our results revealed differential expression of miR-146a-5p, miR-146b-5p, miR-425-3p and miR-24-3p according to treatment response. These results were replicated in two independent clinical trials of MDD, a well-characterized animal model of depression, and post-mortem human brains. Furthermore, using a combination of bioinformatics, mRNA studies and functional in vitro experiments, we showed significant dysregulation of genes involved in MAPK/Wnt signalling pathways. Together, our results indicate that these miRNAs are consistent markers of treatment response and regulators of the MAPK/Wnt systems.

Noncoding RNAs in Depression.

Major depressive disorder (MDD) is a common psychiatric disorder affecting millions of people worldwide, yet its etiology remains elusive. The last decades have seen great advances in our understanding of the genome structure and functional organization. Noncoding RNAs (ncRNAs) are RNAs that do not code for proteins but have important regulatory roles. The investigation of ncRNAs as regulators of gene expression has been a topic of growing interest in health research, including in studies investigating etiological and therapeutic factors in major depression. Several different species of ncRNAs have been identified in association to and have shown to be dysregulated in depressed individuals or in animal models of depression. This review will detail the complex relation between ncRNAs and major depression and the studies that propose mechanisms and pathways that specific ncRNAs may be involved in major depression.

Potential Use of MicroRNA for Monitoring Therapeutic Response to Antidepressants.

Major depressive disorder (MDD) is a serious and common psychiatric disorder that affects millions of people worldwide. The most common treatment methods for MDD are antidepressant drugs, many of which act by regulating monoamines by inhibiting pre-synaptic reuptake and/or by modulating monoamine receptors. Despite advances in antidepressants and other treatment options, therapy is often based on subjective decisions made by the physician. Moreover, it requires time to determine treatment outcome and to define whether the prescribed treatment is effective. Biomarkers may help identify individuals with MDD who are more likely to respond to specific antidepressant treatment and may thus provide more objectivity in treatment decision making. MicroRNA as biomarkers of antidepressant response has engendered substantial enthusiasm. In this review, we give a detailed overview of biomarkers, particularly the major studies that have investigated microRNA in relationship to antidepressant treatment response.