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Molecular Research on Depression

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 12344

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Dr. Magdalena Sowa-Kućma

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Department of Human Physiology, Institute of Medical Sciences, Medical College of Rzeszów University, Kopisto 2a, 35-310 Rzeszow, Poland
Interests: antidepressants; glutamate receptors; epigenetics; depression; animal models of depression; oxidative stress; neuroinflammation
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Dr. Katarzyna Stachowicz

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Guest Editor

Department of Neurobiology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland
Interests: cognition; depression; anxiety; DSCAM; GABA; COX-2; mGluRs
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Special Issue Information

Dear Colleagues,

Depressive disorders are responsible for a significant burden of disease in the human population. This problem affects not only individuals, but also family members and society as a whole. Therefore, it is a serious social and economic problem in the 21st century. For several decades, many theories of depression have been formulated on which modern pharmacotherapy is based. The importance of noradrenergic, serotonergic, dopaminergic or glutamate transmission disturbances in the pathogenesis of depression seems to be undeniable. This is confirmed by drugs that modulate the turnover of these neurotransmitters in the brain and in many cases reduce (or eliminate) symptoms of depression. Unfortunately, 30% (or even more) of depressive patients do not respond to traditional treatment and first-line treatment options. The key to developing new, more effective therapeutic strategies is to understand the molecular mechanisms underlying depressive disorders. In recent years, a large body of work has elucidated some of the molecular/cellular alterations that are critically involved in depression. Improving serotonergic transport to eventually compensate for serotonin deficiencies in the synaptic gap is known to have a health-promoting effect in patients diagnosed with depression. Similarly, regulation of glutamate levels, or dopamine metabolism, have positive effects on aspects related to mood or motivation. Further research is ongoing and brings us closer to a better understanding of the basics of neurotransmission systems and brain circuits regulation in depression. Therefore, we invite and encourage everyone to submit the results and conclusions of new discoveries that may lead to novel therapeutic interventions in the future.

Dr. Magdalena Sowa-Kućma
Dr. Katarzyna Stachowicz
Guest Editors

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Keywords

depression
epigenetics
animal models of depression
serotonin
glutamate
dopamine
neurotrophic factors

Published Papers (7 papers)

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Research

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16 pages, 1600 KiB

Open AccessArticle

Peripheral Upregulation of Parkinson’s Disease-Associated Genes Encoding α-Synuclein, β-Glucocerebrosidase, and Ceramide Glucosyltransferase in Major Depression

by Razvan-Marius Brazdis, Claudia von Zimmermann, Bernd Lenz, Johannes Kornhuber and Christiane Mühle

Int. J. Mol. Sci. 2024, 25(6), 3219; https://doi.org/10.3390/ijms25063219 - 12 Mar 2024

Viewed by 619

Abstract

Due to the high comorbidity of Parkinson’s disease (PD) with major depressive disorder (MDD) and the involvement of sphingolipids in both conditions, we investigated the peripheral expression levels of three primarily PD-associated genes: α-synuclein (SNCA), lysosomal enzyme β-glucocerebrosidase (GBA1), and UDP-glucose ceramide glucosyltransferase (UGCG) in a sex-balanced MDD cohort. Normalized gene expression was determined by quantitative PCR in patients suffering from MDD (unmedicated n = 63, medicated n = 66) and controls (remitted MDD n = 39, healthy subjects n = 61). We observed that expression levels of SNCA (p = 0.036), GBA1 (p = 0.014), and UGCG (p = 0.0002) were higher in currently depressed patients compared to controls and remitted patients, and expression of GBA1 and UGCG decreased in medicated patients during three weeks of therapy. Additionally, in subgroups, expression was positively correlated with the severity of depression and anxiety. Furthermore, we identified correlations between the gene expression levels and PD-related laboratory parameters. Our findings suggest that SNCA, GBA1, and UGCG analysis could be instrumental in the search for biomarkers of MDD and in understanding the overlapping pathological mechanisms underlying neuro-psychiatric diseases. Full article

(This article belongs to the Special Issue Molecular Research on Depression)

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15 pages, 4213 KiB

Open AccessArticle

NLRC5 Deficiency Reduces LPS-Induced Microglial Activation via Inhibition of NF-κB Signaling and Ameliorates Mice’s Depressive-like Behavior

by Chen Sun, Yuqing Shen, Piaopiao Liu, Yi Shen, Yue Hu, Ping Li, Ying Zhang, Fengqin Miao and Jianqiong Zhang

Int. J. Mol. Sci. 2023, 24(17), 13265; https://doi.org/10.3390/ijms241713265 - 26 Aug 2023

Viewed by 1079

Abstract

Microglia are believed to be the key immune effectors of the central immune microenvironment, and their dysregulation is associated with neuroinflammation and mood disorders. Nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain-containing five (NLRC5) is a new member of the Nod-like receptor family. Recently, NLRC5 has been reported to be expressed by microglia. Nonetheless, the exact roles of NLRC5 in microglial activation and its function in depression have not been investigated yet. Herein, we found that reducing NLRC5 decreased lipopolysaccharide (LPS)-induced secretion of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in primary cultured microglia and microglial cell lines but not in bone marrow-derived macrophages (BMDMs). In more detail, reducing NLRC5 diminished the secretion of LPS-induced cytokines by attenuating IKKα/β phosphorylation and inhibiting NF-κB signaling. Moreover, the expression of Nlrc5 in the hippocampus of LPS- or chronic unpredictable mild stress (CUMS)-induced depressive mice was increased. In line with the in vitro findings, Nlrc5 deficiency inhibited microglial activation in the mouse hippocampus and improved LPS- or CUMS-induced depressive-like behaviors. In summary, we demonstrated the critical role of NLRC5 in LPS-induced microglial activation and LPS- or CUMS-induced depressive mouse models. Full article

(This article belongs to the Special Issue Molecular Research on Depression)

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15 pages, 4052 KiB

Open AccessArticle

Transthyretin Is Commonly Upregulated in the Hippocampus of Two Stress-Induced Depression Mouse Models

by Hidehito Saito-Takatsuji, Yasuo Yoshitomi, Ryo Yamamoto, Takafumi Furuyama, Yasuhito Ishigaki, Nobuo Kato, Hideto Yonekura and Takayuki Ikeda

Int. J. Mol. Sci. 2023, 24(4), 3736; https://doi.org/10.3390/ijms24043736 - 13 Feb 2023

Viewed by 1926

Abstract

Chronic stress can affect gene expression in the hippocampus, which alters neural and cerebrovascular functions, thereby contributing to the development of mental disorders such as depression. Although several differentially expressed genes in the depressed brain have been reported, gene expression changes in the stressed brain remain underexplored. Therefore, this study examines hippocampal gene expression in two mouse models of depression induced by forced swim stress (FSS) and repeated social defeat stress (R-SDS). Transthyretin (Ttr) was commonly upregulated in the hippocampus of both mouse models, as determined by microarray, RT-qPCR, and Western blot analyses. Evaluation of the effects of overexpressed Ttr in the hippocampus using adeno-associated virus-mediated gene transfer revealed that TTR overexpression induced depression-like behavior and upregulation of Lcn2 and several proinflammatory genes (Icam1 and Vcam1) in the hippocampus. Upregulation of these inflammation-related genes was confirmed in the hippocampus obtained from mice vulnerable to R-SDS. These results suggest that chronic stress upregulates Ttr expression in the hippocampus and that Ttr upregulation may be involved in the induction of depression-like behavior. Full article

(This article belongs to the Special Issue Molecular Research on Depression)

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17 pages, 5529 KiB

Open AccessArticle

Deciphering the Effect of Different Genetic Variants on Hippocampal Subfield Volumes in the General Population

by Kevin Kirchner, Linda Garvert, Katharina Wittfeld, Sabine Ameling, Robin Bülow, Henriette Meyer zu Schwabedissen, Matthias Nauck, Henry Völzke, Hans J. Grabe and Sandra Van der Auwera

Int. J. Mol. Sci. 2023, 24(2), 1120; https://doi.org/10.3390/ijms24021120 - 06 Jan 2023

Cited by 4 | Viewed by 1797

Abstract

The aim of this study was to disentangle the effects of various genetic factors on hippocampal subfield volumes using three different approaches: a biologically driven candidate gene approach, a hypothesis-free GWAS approach, and a polygenic approach, where AD risk alleles are combined with a polygenic risk score (PRS). The impact of these genetic factors was investigated in a large dementia-free general population cohort from the Study of Health in Pomerania (SHIP, n = 1806). Analyses were performed using linear regression models adjusted for biological and environmental risk factors. Hippocampus subfield volume alterations were found for APOE ε4, BDNF Val, and 5-HTTLPR L allele carriers. In addition, we were able to replicate GWAS findings, especially for rs17178139 (MSRB3), rs1861979 (DPP4), rs7873551 (ASTN2), and rs572246240 (MAST4). Interaction analyses between the significant SNPs as well as the PRS for AD revealed no significant results. Our results confirm that hippocampal volume reductions are influenced by genetic variation, and that different variants reveal different association patterns that can be linked to biological processes in neurodegeneration. Thus, this study underlines the importance of specific genetic analyses in the quest for acquiring deeper insights into the biology of hippocampal volume loss, memory impairment, depression, and neurodegenerative diseases. Full article

(This article belongs to the Special Issue Molecular Research on Depression)

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16 pages, 6428 KiB

Open AccessArticle

Relationship between Urinary Metabolomic Profiles and Depressive Episode in Antarctica

by Kazuhiko Kasuya, Satoshi Imura, Takashi Ishikawa, Masahiro Sugimoto and Takeshi Inoue

Int. J. Mol. Sci. 2023, 24(2), 943; https://doi.org/10.3390/ijms24020943 - 04 Jan 2023

Viewed by 1481

Abstract

Antarctic expeditions have a high risk of participant depression owing to long stays and isolated environments. By quantifying the stress state and changes in biomolecules over time before the onset of depressive symptoms, predictive markers of depression can be explored. Here, we evaluated the psychological changes in 30 participants in the Japanese Antarctic Research Expedition using the Patient Health Questionnaire-9 (PHQ-9). Urinary samples were collected every three months for a year, and comprehensive urinary metabolomic profiles were quantified using liquid chromatography time-of-flight mass spectrometry. Five participants showed major depressive episodes (PHQ-9 ≥ 10) at 12 months. The urinary metabolites between these participants and the 25 unaffected participants were compared at individual metabolite and pathway levels. The individual comparisons showed the most significant differences at 12 months in 14 metabolites, including ornithine and beta-alanine. Data from shorter stays showed less significant differences. In contrast, pathway and enrichment analyses showed the most significant difference at three months and a less significant difference at longer stays. These time transitions of urinary metabolites could help in the development of urinary biomarkers to detect subjects with depressive episodes at an early stage. Full article

(This article belongs to the Special Issue Molecular Research on Depression)

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19 pages, 355 KiB

Open AccessArticle

Macrophage Migration Inhibitory Factor in Major Depressive Disorder: A Multilevel Pilot Study

by Caroline Swoboda, Lena Deloch, Claudia von Zimmermann, Tanja Richter-Schmidinger, Bernd Lenz, Johannes Kornhuber and Christiane Mühle

Int. J. Mol. Sci. 2022, 23(24), 15460; https://doi.org/10.3390/ijms232415460 - 07 Dec 2022

Cited by 5 | Viewed by 1477

Abstract

Macrophage migration inhibitory factor (MIF) is a controversially discussed inflammatory marker in major depressive disorder (MDD). While some studies show an association of high MIF protein levels with depression, animal models have yielded conflicting results. Thus, it remains elusive as to whether MIF plays an anti- or pro-depressive role. Therefore, we aimed to examine the potential of MIF at the genetic, expression and protein levels as a risk factor and biomarker to diagnose, monitor, or predict the course of MDD. Patients with a current major depressive episode (n = 66 with, and n = 63 without, prior medication) and remitted patients (n = 39) were compared with healthy controls (n = 61). Currently depressed patients provided a second blood sample after three weeks of therapy. Depression severity was assessed by self-evaluation and clinician rating scales. We genotyped for three MIF polymorphisms and analyzed peripheral MIF expression and serum levels. The absence of minor allele homozygous individuals in the large group of 96 female patients compared with 10–16% in female controls suggests a protective effect for MDD, which was not observed in the male group. There were no significant group differences of protein and expression levels, however, both showed predictive potential for the course of depression severity in some subgroups. While MIF protein levels, but not MIF expression, decreased during treatment, they were not associated with changes in depression severity. This project is the first to investigate three biological levels of MIF in depression. The data hint toward a genetic effect in women, but do not provide robust evidence for the utility of MIF as a biomarker for the diagnosis or monitoring of MDD. The observed predictive potential requires further analysis, emphasizing future attention to confounding factors such as sex and premedication. Full article

(This article belongs to the Special Issue Molecular Research on Depression)

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16 pages, 904 KiB

Open AccessReview

The Role of Genetics in the Development and Pharmacotherapy of Depression and Its Impact on Drug Discovery

by Agata Zięba, Dariusz Matosiuk and Agnieszka A. Kaczor

Int. J. Mol. Sci. 2023, 24(3), 2946; https://doi.org/10.3390/ijms24032946 - 02 Feb 2023

Cited by 2 | Viewed by 3138

Abstract

Complex disorders, such as depression, remain a mystery for scientists. Although genetic factors are considered important for the prediction of one’s vulnerability, it is hard to estimate the exact risk for a patient to develop depression, based only on one category of vulnerability criteria. Genetic factors also regulate drug metabolism, and when they are identified in a specific combination, may result in increased drug resistance. A proper understanding of the genetic basis of depression assists in the development of novel promising medications and effective disorder management schemes. This review aims to analyze the recent literature focusing on the correlation between specific genes and the occurrence of depression. Moreover, certain aspects targeting a high drug resistance identified among patients suffering from major depressive disorder were highlighted in this manuscript. An expected direction of future drug discovery campaigns was also discussed. Full article

(This article belongs to the Special Issue Molecular Research on Depression)

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