International Journal of Molecular Sciences

Editorial

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6 pages, 207 KiB

Open AccessEditorial

Molecular Psychiatry: Trends and Study Examples

by Theo Rein and Gabriel R. Fries

Int. J. Mol. Sci. 2020, 21(2), 459; https://doi.org/10.3390/ijms21020459 - 10 Jan 2020

Cited by 1 | Viewed by 2229

Abstract

In contrast to about 20–30 years ago, the concept that psychiatric diseases have a molecular basis is now widely accepted [...] Full article

(This article belongs to the Special Issue Molecular Psychiatry)

Research

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14 pages, 3097 KiB

Open AccessArticle

Social Defeat Modulates T Helper Cell Percentages in Stress Susceptible and Resilient Mice

by Oliver Ambrée, Christina Ruland, Peter Zwanzger, Luisa Klotz, Bernhard T Baune, Volker Arolt, Stefanie Scheu and Judith Alferink

Int. J. Mol. Sci. 2019, 20(14), 3512; https://doi.org/10.3390/ijms20143512 - 17 Jul 2019

Cited by 37 | Viewed by 5137

Abstract

Altered adaptive immunity involving T lymphocytes has been found in depressed patients and in stress-induced depression-like behavior in animal models. Peripheral T cells play important roles in homeostasis and function of the central nervous system and thus modulate behavior. However, the T cell [...] Read more.

Altered adaptive immunity involving T lymphocytes has been found in depressed patients and in stress-induced depression-like behavior in animal models. Peripheral T cells play important roles in homeostasis and function of the central nervous system and thus modulate behavior. However, the T cell phenotype and function associated with susceptibility and resilience to depression remain largely unknown. Here, we characterized splenic T cells in susceptible and resilient mice after 10 days of social defeat stress (SDS). We found equally decreased T cell frequencies and comparably altered expression levels of genes associated with T helper (Th) cell function in resilient and susceptible mice. Interleukin (IL)-17 producing CD4⁺ and CD8⁺ T cell numbers in the spleen were significantly increased in susceptible mice. These animals further exhibited significantly reduced numbers of regulatory T cells (T_reg) and decreased gene expression levels of TGF-β. Mice with enhanced Th17 differentiation induced by conditional deletion of PPARγ in CD4⁺ cells (CD4-PPARγ^KO), an inhibitor of Th17 development, were equally susceptible to SDS when compared to CD4-PPARγ^WT controls. These data indicate that enhanced Th17 differentiation alone does not alter stress vulnerability. Thus, SDS promotes Th17 cell and suppresses T_reg cell differentiation predominantly in susceptible mice with yet unknown effects in immune responses after stress exposure. Full article

(This article belongs to the Special Issue Molecular Psychiatry)

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7 pages, 225 KiB

Open AccessCommunication

Alpha-Synuclein RNA Expression is Increased in Major Depression

by Andrea Rotter, Bernd Lenz, Ruben Pitsch, Tanja Richter-Schmidinger, Johannes Kornhuber and Cosima Rhein

Int. J. Mol. Sci. 2019, 20(8), 2029; https://doi.org/10.3390/ijms20082029 - 25 Apr 2019

Cited by 23 | Viewed by 4054

Abstract

Alpha-synuclein (SNCA) is a small membrane protein that plays an important role in neuro-psychiatric diseases. It is best known for its abnormal subcellular aggregation in Lewy bodies that serves as a hallmark of Parkinson’s disease (PD). Due to the high comorbidity of PD [...] Read more.

Alpha-synuclein (SNCA) is a small membrane protein that plays an important role in neuro-psychiatric diseases. It is best known for its abnormal subcellular aggregation in Lewy bodies that serves as a hallmark of Parkinson’s disease (PD). Due to the high comorbidity of PD with depression, we investigated the role of SNCA in patients suffering from major depressive disorder (MDD). SNCA mRNA expression levels were analyzed in peripheral blood cells of MDD patients and a healthy control group. SNCA mRNA expression was positively correlated with severity of depression as indicated by psychometric assessment. We found a significant increase in SNCA mRNA expression levels in severely depressed patients compared with controls. Thus, SNCA analysis could be a helpful target in the search for biomarkers of MDD. Full article

(This article belongs to the Special Issue Molecular Psychiatry)

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19 pages, 1301 KiB

Open AccessArticle

The Association Between Affective Temperament Traits and Dopamine Genes in Obese Population

by Natalia Lesiewska, Alina Borkowska, Roman Junik, Anna Kamińska, Joanna Pulkowska-Ulfig, Andrzej Tretyn and Maciej Bieliński

Int. J. Mol. Sci. 2019, 20(8), 1847; https://doi.org/10.3390/ijms20081847 - 15 Apr 2019

Cited by 7 | Viewed by 3582

Abstract

Studies indicate the heritable nature of affective temperament, which shows personality traits predisposing to the development of mental disorders. Dopaminergic gene polymorphisms such as DRD4, COMTVal158Met, and DAT1 have been linked to affective disorders in obesity. Due to possible correlation between [...] Read more.

Studies indicate the heritable nature of affective temperament, which shows personality traits predisposing to the development of mental disorders. Dopaminergic gene polymorphisms such as DRD4, COMTVal158Met, and DAT1 have been linked to affective disorders in obesity. Due to possible correlation between the aforementioned polymorphisms and the affective temperament, the aim of our research was to investigate this connection in an obese population. The study enrolled 245 obese patients (178 females; 67 males). The affective temperament was assessed using the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego autoquestionnaire (TEMPS-A). Genetic polymorphisms of DAT1, COMTVal158Met and DRD4 were collected from peripheral blood sample and determined using a polymerase chain reaction (PCR). Only in COMT polymorphisms, the cyclothymic and irritable dimensions were significantly associated with Met/Val carriers (p = 0.04; p = 0.01). Another interesting finding was the correlation between the affective temperament and age in men and women. We assume that dopamine transmission in heterozygotes of COMT may determine the role of the affective temperament in obese persons. Dopaminergic transmission modulated by COMT may be responsible for a greater temperament expression in obese individuals. To our knowledge, this is the first study describing the role of affective temperament in the obese population, but more research is needed in this regard. Full article

(This article belongs to the Special Issue Molecular Psychiatry)

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13 pages, 1640 KiB

Open AccessArticle

Mechanistic Insights in NeuroD Potentiation of Mineralocorticoid Receptor Signaling

by Lisa T. C. M. van Weert, Jacobus C. Buurstede, Hetty C. M. Sips, Isabel M. Mol, Tanvi Puri, Ruth Damsteegt, Benno Roozendaal, R. Angela Sarabdjitsingh and Onno C. Meijer

Int. J. Mol. Sci. 2019, 20(7), 1575; https://doi.org/10.3390/ijms20071575 - 29 Mar 2019

Cited by 16 | Viewed by 3834

Abstract

Mineralocorticoid receptor (MR)-mediated signaling in the brain has been suggested as a protective factor in the development of psychopathology, in particular mood disorders. We recently identified genomic loci at which either MR or the closely related glucocorticoid receptor (GR) binds selectively, and found [...] Read more.

Mineralocorticoid receptor (MR)-mediated signaling in the brain has been suggested as a protective factor in the development of psychopathology, in particular mood disorders. We recently identified genomic loci at which either MR or the closely related glucocorticoid receptor (GR) binds selectively, and found members of the NeuroD transcription factor family to be specifically associated with MR-bound DNA in the rat hippocampus. We show here using forebrain-specific MR knockout mice that GR binding to MR/GR joint target loci is not affected in any major way in the absence of MR. Neurod2 binding was also independent of MR binding. Moreover, functional comparison with MyoD family members indicates that it is the chromatin remodeling aspect of NeuroD, rather than its direct stimulation of transcription, that is responsible for potentiation of MR-mediated transcription. These findings suggest that NeuroD acts in a permissive way to enhance MR-mediated transcription, and they argue against competition for DNA binding as a mechanism of MR- over GR-specific binding. Full article

(This article belongs to the Special Issue Molecular Psychiatry)

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12 pages, 730 KiB

Open AccessArticle

FKBP5 Gene Expression Predicts Antidepressant Treatment Outcome in Depression

by Marcus Ising, Giuseppina Maccarrone, Tanja Brückl, Sandra Scheuer, Johannes Hennings, Florian Holsboer, Christoph W. Turck, Manfred Uhr and Susanne Lucae

Int. J. Mol. Sci. 2019, 20(3), 485; https://doi.org/10.3390/ijms20030485 - 23 Jan 2019

Cited by 44 | Viewed by 7650

Abstract

Adverse experiences and chronic stress are well-known risk factors for the development of major depression, and an impaired stress response regulation is frequently observed in acute depression. Impaired glucocorticoid receptor (GR) signalling plays an important role in these alterations, and a restoration of [...] Read more.

Adverse experiences and chronic stress are well-known risk factors for the development of major depression, and an impaired stress response regulation is frequently observed in acute depression. Impaired glucocorticoid receptor (GR) signalling plays an important role in these alterations, and a restoration of GR signalling appears to be a prerequisite of successful antidepressant treatment. Variants in genes of the stress response regulation contribute to the vulnerability to depression in traumatized subjects. Consistent findings point to an important role of FKBP5, the gene expressing FK506-binding protein 51 (FKBP51), which is a strong inhibitor of the GR, and thus, an important regulator of the stress response. We investigated the role of FKBP5 and FKB51 expression with respect to stress response regulation and antidepressant treatment outcome in depressed patients. This study included 297 inpatients, who participated in the Munich Antidepressant Response Signature (MARS) project and were treated for acute depression. In this open-label study, patients received antidepressant treatment according to the attending doctor’s choice. In addition to the FKBP5 genotype, changes in blood FKBP51 expression during antidepressant treatment were analyzed using RT-PCR and ZeptoMARK^TM reverse phase protein microarray (RPPM). Stress response regulation was evaluated in a subgroup of patients using the combined dexamethasone (dex)/corticotropin releasing hormone (CRH) test. As expected, increased FKBP51 expression was associated with an impaired stress response regulation at baseline and after six weeks was accompanied by an elevated cortisol response to the combined dex/CRH test. Further, we demonstrated an active involvement of FKBP51 in antidepressant treatment outcome. While patients responding to antidepressant treatment had a pronounced reduction of FKBP5 gene and FKBP51 protein expression, increasing expression levels were observed in nonresponders. This effect was moderated by the genotype of the FKBP5 single nucleotide polymorphism (SNP) rs1360780, with carriers of the minor allele showing the most pronounced association. Our findings demonstrate that FKBP5 and, specifically, its expression product FKBP51 are important modulators of antidepressant treatment outcome, pointing to a new, promising target for future antidepressant drug development. Full article

(This article belongs to the Special Issue Molecular Psychiatry)

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13 pages, 857 KiB

Open AccessArticle

Proteomic Studies Reveal Disrupted in Schizophrenia 1 as a Player in Both Neurodevelopment and Synaptic Function

by Adriana Ramos, Carmen Rodríguez-Seoane, Isaac Rosa, Irantzu Gorroño-Etxebarria, Jana Alonso, Sonia Veiga, Carsten Korth, Robert M. Kypta, Ángel García and Jesús R. Requena

Int. J. Mol. Sci. 2019, 20(1), 119; https://doi.org/10.3390/ijms20010119 - 29 Dec 2018

Cited by 4 | Viewed by 4683

Abstract

A balanced chromosomal translocation disrupting DISC1 (Disrupted in Schizophrenia 1) gene has been linked to psychiatric diseases, such as major depression, bipolar disorder and schizophrenia. Since the discovery of this translocation, many studies have focused on understating the role of the truncated isoform [...] Read more.

A balanced chromosomal translocation disrupting DISC1 (Disrupted in Schizophrenia 1) gene has been linked to psychiatric diseases, such as major depression, bipolar disorder and schizophrenia. Since the discovery of this translocation, many studies have focused on understating the role of the truncated isoform of DISC1, hypothesizing that the gain of function of this protein could be behind the neurobiology of mental conditions, but not so many studies have focused in the mechanisms impaired due to its loss of function. For that reason, we performed an analysis on the cellular proteome of primary neurons in which DISC1 was knocked down with the goal of identifying relevant pathways directly affected by DISC1 loss of function. Using an unbiased proteomic approach, we found that the expression of 31 proteins related to neurodevelopment (e.g., CRMP-2, stathmin) and synaptic function (e.g., MUNC-18, NCS-1) is altered by DISC1 in primary mouse neurons. Hence, this study reinforces the idea that DISC1 is a unifying regulator of both neurodevelopment and synaptic function, thereby providing a link between these two key anatomical and cellular circuitries. Full article

(This article belongs to the Special Issue Molecular Psychiatry)

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19 pages, 1473 KiB

Open AccessArticle

Peripheral Acid Sphingomyelinase Activity Is Associated with Biomarkers and Phenotypes of Alcohol Use and Dependence in Patients and Healthy Controls

by Christiane Mühle, Christian Weinland, Erich Gulbins, Bernd Lenz and Johannes Kornhuber

Int. J. Mol. Sci. 2018, 19(12), 4028; https://doi.org/10.3390/ijms19124028 - 13 Dec 2018

Cited by 30 | Viewed by 3872

Abstract

By catalyzing the hydrolysis of sphingomyelin into ceramide, acid sphingomyelinase (ASM) changes the local composition of the plasma membrane with effects on receptor-mediated signaling. Altered enzyme activities have been noted in common human diseases, including alcohol dependence. However, the underlying mechanisms remain largely [...] Read more.

By catalyzing the hydrolysis of sphingomyelin into ceramide, acid sphingomyelinase (ASM) changes the local composition of the plasma membrane with effects on receptor-mediated signaling. Altered enzyme activities have been noted in common human diseases, including alcohol dependence. However, the underlying mechanisms remain largely unresolved. Blood samples were collected from early-abstinent alcohol-dependent in-patients (n[♂] = 113, n[♀] = 87) and matched healthy controls (n[♂] = 133, n[♀] = 107), and analyzed for routine blood parameters and serum ASM activity. We confirmed increased secretory ASM activities in alcohol-dependent patients compared to healthy control subjects, which decreased slightly during detoxification. ASM activity correlated positively with blood alcohol concentration, withdrawal severity, biomarkers of alcohol dependence (liver enzyme activities of gamma-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase; homocysteine, carbohydrate-deficient transferrin; mean corpuscular volume, and creatine kinase). ASM activity correlated negatively with leukocyte and thrombocyte counts. ASM and gamma-glutamyl transferase were also associated in healthy subjects. Most effects were similar for males and females with different strengths. We describe previously unreported associations between ASM activity and markers of liver damage and myelosuppression. Further research should investigate whether this relationship is causal, or whether these parameters are part of a common pathway in order to gain insights into underlying mechanisms and develop clinical applications. Full article

(This article belongs to the Special Issue Molecular Psychiatry)

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30 pages, 5163 KiB

Open AccessArticle

The Stress-Inducible Protein DRR1 Exerts Distinct Effects on Actin Dynamics

by Anja Kretzschmar, Jan-Philip Schülke, Mercè Masana, Katharina Dürre, Marianne B. Müller, Andreas R. Bausch and Theo Rein

Int. J. Mol. Sci. 2018, 19(12), 3993; https://doi.org/10.3390/ijms19123993 - 11 Dec 2018

Cited by 10 | Viewed by 4835

Abstract

Cytoskeletal dynamics are pivotal to memory, learning, and stress physiology, and thus psychiatric diseases. Downregulated in renal cell carcinoma 1 (DRR1) protein was characterized as the link between stress, actin dynamics, neuronal function, and cognition. To elucidate the underlying molecular mechanisms, we undertook [...] Read more.

Cytoskeletal dynamics are pivotal to memory, learning, and stress physiology, and thus psychiatric diseases. Downregulated in renal cell carcinoma 1 (DRR1) protein was characterized as the link between stress, actin dynamics, neuronal function, and cognition. To elucidate the underlying molecular mechanisms, we undertook a domain analysis of DRR1 and probed the effects on actin binding, polymerization, and bundling, as well as on actin-dependent cellular processes. Methods: DRR1 domains were cloned and expressed as recombinant proteins to perform in vitro analysis of actin dynamics (binding, bundling, polymerization, and nucleation). Cellular actin-dependent processes were analyzed in transfected HeLa cells with fluorescence recovery after photobleaching (FRAP) and confocal microscopy. Results: DRR1 features an actin binding site at each terminus, separated by a coiled coil domain. DRR1 enhances actin bundling, the cellular F-actin content, and serum response factor (SRF)-dependent transcription, while it diminishes actin filament elongation, cell spreading, and actin treadmilling. We also provide evidence for a nucleation effect of DRR1. Blocking of pointed end elongation by addition of profilin indicates DRR1 as a novel barbed end capping factor. Conclusions: DRR1 impacts actin dynamics in several ways with implications for cytoskeletal dynamics in stress physiology and pathophysiology. Full article

(This article belongs to the Special Issue Molecular Psychiatry)

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27 pages, 4081 KiB

Open AccessArticle

Effect of Acute Stress on the Expression of BDNF, trkB, and PSA-NCAM in the Hippocampus of the Roman Rats: A Genetic Model of Vulnerability/Resistance to Stress-Induced Depression

by Maria Pina Serra, Laura Poddighe, Marianna Boi, Francesco Sanna, Maria Antonietta Piludu, Fabrizio Sanna, Maria G. Corda, Osvaldo Giorgi and Marina Quartu

Int. J. Mol. Sci. 2018, 19(12), 3745; https://doi.org/10.3390/ijms19123745 - 24 Nov 2018

Cited by 24 | Viewed by 7037

Abstract

The Roman High-Avoidance (RHA) and the Roman Low-Avoidance (RLA) rats, represent two psychogenetically-selected lines that are, respectively, resistant and prone to displaying depression-like behavior, induced by stressors. In the view of the key role played by the neurotrophic factors and neuronal plasticity, in [...] Read more.

The Roman High-Avoidance (RHA) and the Roman Low-Avoidance (RLA) rats, represent two psychogenetically-selected lines that are, respectively, resistant and prone to displaying depression-like behavior, induced by stressors. In the view of the key role played by the neurotrophic factors and neuronal plasticity, in the pathophysiology of depression, we aimed at assessing the effects of acute stress, i.e., forced swimming (FS), on the expression of brain-derived neurotrophic factor (BDNF), its trkB receptor, and the Polysialilated-Neural Cell Adhesion Molecule (PSA-NCAM), in the dorsal (dHC) and ventral (vHC) hippocampus of the RHA and the RLA rats, by means of western blot and immunohistochemical assays. A 15 min session of FS elicited different changes in the expression of BDNF in the dHC and the vHC. In RLA rats, an increment in the CA2 and CA3 subfields of the dHC, and a decrease in the CA1 and CA3 subfields and the dentate gyrus (DG) of the vHC, was observed. On the other hand, in the RHA rats, no significant changes in the BDNF levels was seen in the dHC and there was a decrease in the CA1, CA3, and DG of the vHC. Line-related changes were also observed in the expression of trkB and PSA-NCAM. The results are consistent with the hypothesis that the differences in the BDNF/trkB signaling and neuroplastic mechanisms are involved in the susceptibility of RLA rats and resistance of RHA rats to stress-induced depression. Full article

(This article belongs to the Special Issue Molecular Psychiatry)

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15 pages, 2517 KiB

Open AccessArticle

Comparative Evaluation of Machine Learning Strategies for Analyzing Big Data in Psychiatry

by Han Cao, Andreas Meyer-Lindenberg and Emanuel Schwarz

Int. J. Mol. Sci. 2018, 19(11), 3387; https://doi.org/10.3390/ijms19113387 - 29 Oct 2018

Cited by 15 | Viewed by 5022

Abstract

The requirement of innovative big data analytics has become a critical success factor for research in biological psychiatry. Integrative analyses across distributed data resources are considered essential for untangling the biological complexity of mental illnesses. However, little is known about algorithm properties for [...] Read more.

The requirement of innovative big data analytics has become a critical success factor for research in biological psychiatry. Integrative analyses across distributed data resources are considered essential for untangling the biological complexity of mental illnesses. However, little is known about algorithm properties for such integrative machine learning. Here, we performed a comparative analysis of eight machine learning algorithms for identification of reproducible biological fingerprints across data sources, using five transcriptome-wide expression datasets of schizophrenia patients and controls as a use case. We found that multi-task learning (MTL) with network structure (MTL_NET) showed superior accuracy compared to other MTL formulations as well as single task learning, and tied performance with support vector machines (SVM). Compared to SVM, MTL_NET showed significant benefits regarding the variability of accuracy estimates, as well as its robustness to cross-dataset and sampling variability. These results support the utility of this algorithm as a flexible tool for integrative machine learning in psychiatry. Full article

(This article belongs to the Special Issue Molecular Psychiatry)

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12 pages, 624 KiB

Open AccessArticle

Classical Risk Factors and Inflammatory Biomarkers: One of the Missing Biological Links between Cardiovascular Disease and Major Depressive Disorder

by Thomas C. Baghai, Gabriella Varallo-Bedarida, Christoph Born, Sibylle Häfner, Cornelius Schüle, Daniela Eser, Peter Zill, André Manook, Johannes Weigl, Somayeh Jooyandeh, Caroline Nothdurfter, Clemens Von Schacky, Brigitta Bondy and Rainer Rupprecht

Int. J. Mol. Sci. 2018, 19(6), 1740; https://doi.org/10.3390/ijms19061740 - 12 Jun 2018

Cited by 44 | Viewed by 5616

Abstract

Background: Cardiovascular disorders (CVD) and major depressive disorder (MDD) are the most frequent diseases worldwide responsible for premature death and disability. Behavioral and immunological variables influence the pathophysiology of both disorders. We therefore determined frequency and severity of MDD in CVD and studied [...] Read more.

Background: Cardiovascular disorders (CVD) and major depressive disorder (MDD) are the most frequent diseases worldwide responsible for premature death and disability. Behavioral and immunological variables influence the pathophysiology of both disorders. We therefore determined frequency and severity of MDD in CVD and studied whether MDD without CVD or other somatic diseases influences classical and inflammatory biomarkers of cardiovascular risk. In addition, we investigated the influence of proinflammatory cytokines on antidepressant treatment outcome. Methods: In a case-control design, 310 adults (MDD patients without CVD, CVD patients, and cardiologically and psychiatrically healthy matched controls) were investigated. MDD patients were recruited after admission in a psychiatric university hospital. Primary outcome criteria were clinical depression ratings (HAM-D scale), vital signs, classical cardiovascular risk factors and inflammatory biomarkers which were compared between MDD patients and healthy controls. Results: We detected an enhanced cardiovascular risk in MDD. Untreated prehypertension and signs directing to a metabolic syndrome were detected in MDD. Significantly higher inflammatory biomarkers such as the high sensitivity C-reaktive protein (hsCRP) and proinflammatory acute phase cytokines interleukine-1β (IL-1β) and interleukine-6 (IL-6) underlined the higher cardiovascular risk in physically healthy MDD patients. Surprisingly, high inflammation markers before treatment were associated with better clinical outcome and faster remission. The rate of MDD in CVD patients was high. Conclusions: Patients suffering from MDD are at specific risk for CVD. Precise detection of cardiovascular risks in MDD beyond classical risk factors is warranted to allow effective prophylaxis and treatment of both conditions. Future studies of prophylactic interventions may help to provide a basis for prophylactic treatment of both MDD and CVD. In addition, the high risk for MDD in CVD patients was confirmed and underlines the requirement for clinical attention. Full article

(This article belongs to the Special Issue Molecular Psychiatry)

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Review

Jump to: Editorial, Research

17 pages, 265 KiB

Open AccessReview

The Role of Chemokines in the Pathophysiology of Major Depressive Disorder

by Vladimir M. Milenkovic, Evan H. Stanton, Caroline Nothdurfter, Rainer Rupprecht and Christian H. Wetzel

Int. J. Mol. Sci. 2019, 20(9), 2283; https://doi.org/10.3390/ijms20092283 - 9 May 2019

Cited by 102 | Viewed by 8927

Abstract

Major depressive disorder (MDD) is a debilitating condition, whose high prevalence and multisymptomatic nature set its standing as a leading contributor to global disability. To better understand this psychiatric disease, various pathophysiological mechanisms have been proposed, including changes in monoaminergic neurotransmission, imbalance of [...] Read more.

Major depressive disorder (MDD) is a debilitating condition, whose high prevalence and multisymptomatic nature set its standing as a leading contributor to global disability. To better understand this psychiatric disease, various pathophysiological mechanisms have been proposed, including changes in monoaminergic neurotransmission, imbalance of excitatory and inhibitory signaling in the brain, hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, and abnormalities in normal neurogenesis. While previous findings led to a deeper understanding of the disease, the pathogenesis of MDD has not yet been elucidated. Accumulating evidence has confirmed the association between chronic inflammation and MDD, which is manifested by increased levels of the C-reactive protein, as well as pro-inflammatory cytokines, such as Interleukin 1 beta, Interleukin 6, and the Tumor necrosis factor alpha. Furthermore, recent findings have implicated a related family of cytokines with chemotactic properties, known collectively as chemokines, in many neuroimmune processes relevant to psychiatric disorders. Chemokines are small (8–12 kDa) chemotactic cytokines, which are known to play roles in direct chemotaxis induction, leukocyte and macrophage migration, and inflammatory response propagation. The inflammatory chemokines possess the ability to induce migration of immune cells to the infection site, whereas their homeostatic chemokine counterparts are responsible for recruiting cells for their repair and maintenance. To further support the role of chemokines as central elements to healthy bodily function, recent studies suggest that these proteins demonstrate novel, brain-specific mechanisms including the modulation of neuroendocrine functions, chemotaxis, cell adhesion, and neuroinflammation. Elevated levels of chemokines in patient-derived serum have been detected in individuals diagnosed with major depressive disorder, bipolar disorder, and schizophrenia. Furthermore, despite the considerable heterogeneity of experimental samples and methodologies, existing biomarker studies have clearly demonstrated the important role of chemokines in the pathophysiology of psychiatric disorders. The purpose of this review is to summarize the data from contemporary experimental and clinical studies, and to evaluate available evidence for the role of chemokines in the central nervous system (CNS) under physiological and pathophysiological conditions. In light of recent results, chemokines could be considered as possible peripheral markers of psychiatric disorders, and/or targets for treating depressive disorders. Full article

(This article belongs to the Special Issue Molecular Psychiatry)

17 pages, 749 KiB

Open AccessReview

Decoding the Mechanism of Action of Rapid-Acting Antidepressant Treatment Strategies: Does Gender Matter?

by David P. Herzog, Gregers Wegener, Klaus Lieb, Marianne B. Müller and Giulia Treccani

Int. J. Mol. Sci. 2019, 20(4), 949; https://doi.org/10.3390/ijms20040949 - 22 Feb 2019

Cited by 26 | Viewed by 6206

Abstract

Gender differences play a pivotal role in the pathophysiology and treatment of major depressive disorder. This is strongly supported by a mean 2:1 female-male ratio of depression consistently observed throughout studies in developed nations. Considering the urgent need to tailor individualized treatment strategies [...] Read more.

Gender differences play a pivotal role in the pathophysiology and treatment of major depressive disorder. This is strongly supported by a mean 2:1 female-male ratio of depression consistently observed throughout studies in developed nations. Considering the urgent need to tailor individualized treatment strategies to fight depression more efficiently, a more precise understanding of gender-specific aspects in the pathophysiology and treatment of depressive disorders is fundamental. However, current treatment guidelines almost entirely neglect gender as a potentially relevant factor. Similarly, the vast majority of animal experiments analysing antidepressant treatment in rodent models exclusively uses male animals and does not consider gender-specific effects. Based on the growing interest in innovative and rapid-acting treatment approaches in depression, such as the administration of ketamine, its metabolites or electroconvulsive therapy, this review article summarizes the evidence supporting the importance of gender in modulating response to rapid acting antidepressant treatment. We provide an overview on the current state of knowledge and propose a framework for rodent experiments to ultimately decode gender-dependent differences in molecular and behavioural mechanisms involved in shaping treatment response. Full article

(This article belongs to the Special Issue Molecular Psychiatry)

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14 pages, 875 KiB

Open AccessReview

Depression and Sleep

by Axel Steiger and Marcel Pawlowski

Int. J. Mol. Sci. 2019, 20(3), 607; https://doi.org/10.3390/ijms20030607 - 31 Jan 2019

Cited by 165 | Viewed by 30178

Abstract

Impaired sleep is both a risk factor and a symptom of depression. Objective sleep is assessed using the sleep electroencephalogram (EEG). Characteristic sleep-EEG changes in patients with depression include disinhibition of rapid eye movement (REM) sleep, changes of sleep continuity, and impaired non-REM [...] Read more.

Impaired sleep is both a risk factor and a symptom of depression. Objective sleep is assessed using the sleep electroencephalogram (EEG). Characteristic sleep-EEG changes in patients with depression include disinhibition of rapid eye movement (REM) sleep, changes of sleep continuity, and impaired non-REM sleep. Most antidepressants suppress REM sleep both in healthy volunteers and depressed patients. Various sleep-EEG variables may be suitable as biomarkers for diagnosis, prognosis, and prediction of therapy response in depression. In family studies of depression, enhanced REM density, a measure for frequency of rapid eye movements, is characteristic for an endophenotype. Cordance is an EEG measure distinctly correlated with regional brain perfusion. Prefrontal theta cordance, derived from REM sleep, appears to be a biomarker of antidepressant treatment response. Some predictive sleep-EEG markers of depression appear to be related to hypothalamo-pituitary-adrenocortical system activity. Full article

(This article belongs to the Special Issue Molecular Psychiatry)

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14 pages, 677 KiB

Open AccessReview

Hsp90 Heterocomplexes Regulate Steroid Hormone Receptors: From Stress Response to Psychiatric Disease

by Jeremy D. Baker, Ilayda Ozsan, Santiago Rodriguez Ospina, Danielle Gulick and Laura J. Blair

Int. J. Mol. Sci. 2019, 20(1), 79; https://doi.org/10.3390/ijms20010079 - 25 Dec 2018

Cited by 46 | Viewed by 7833

Abstract

The hypothalamus-pituitary-adrenal (HPA) axis directly controls the stress response. Dysregulation of this neuroendocrine system is a common feature among psychiatric disorders. Steroid hormone receptors, like glucocorticoid receptor (GR), function as transcription factors of a diverse set of genes upon activation. This activity is [...] Read more.

The hypothalamus-pituitary-adrenal (HPA) axis directly controls the stress response. Dysregulation of this neuroendocrine system is a common feature among psychiatric disorders. Steroid hormone receptors, like glucocorticoid receptor (GR), function as transcription factors of a diverse set of genes upon activation. This activity is regulated by molecular chaperone heterocomplexes. Much is known about the structure and function of these GR/heterocomplexes. There is strong evidence suggesting altered regulation of steroid receptor hormones by chaperones, particularly the 51 kDa FK506-binding protein (FKBP51), may work with environmental factors to increase susceptibility to various psychiatric illnesses including post-traumatic stress disorder (PTSD), major depressive disorder (MDD), and anxiety. This review highlights the regulation of steroid receptor dynamics by the 90kDa heat shock protein (Hsp90)/cochaperone heterocomplexes with an in depth look at how the structural regulation and imbalances in cochaperones can cause functional effects on GR activity. Links between the stress response and circadian systems and the development of novel chaperone-targeting therapeutics are also discussed. Full article

(This article belongs to the Special Issue Molecular Psychiatry)

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31 pages, 835 KiB

Open AccessReview

Childhood-Onset Schizophrenia: Insights from Induced Pluripotent Stem Cells

by Anke Hoffmann, Michael Ziller and Dietmar Spengler

Int. J. Mol. Sci. 2018, 19(12), 3829; https://doi.org/10.3390/ijms19123829 - 30 Nov 2018

Cited by 20 | Viewed by 6865

Abstract

Childhood-onset schizophrenia (COS) is a rare psychiatric disorder characterized by earlier onset, more severe course, and poorer outcome relative to adult-onset schizophrenia (AOS). Even though, clinical, neuroimaging, and genetic studies support that COS is continuous to AOS. Early neurodevelopmental deviations in COS are [...] Read more.

Childhood-onset schizophrenia (COS) is a rare psychiatric disorder characterized by earlier onset, more severe course, and poorer outcome relative to adult-onset schizophrenia (AOS). Even though, clinical, neuroimaging, and genetic studies support that COS is continuous to AOS. Early neurodevelopmental deviations in COS are thought to be significantly mediated through poorly understood genetic risk factors that may also predispose to long-term outcome. In this review, we discuss findings from induced pluripotent stem cells (iPSCs) that allow the generation of disease-relevant cell types from early brain development. Because iPSCs capture each donor’s genotype, case/control studies can uncover molecular and cellular underpinnings of COS. Indeed, recent studies identified alterations in neural progenitor and neuronal cell function, comprising dendrites, synapses, electrical activity, glutamate signaling, and miRNA expression. Interestingly, transcriptional signatures of iPSC-derived cells from patients with COS showed concordance with postmortem brain samples from SCZ, indicating that changes in vitro may recapitulate changes from the diseased brain. Considering this progress, we discuss also current caveats from the field of iPSC-based disease modeling and how to proceed from basic studies to improved diagnosis and treatment of COS. Full article

(This article belongs to the Special Issue Molecular Psychiatry)

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13 pages, 1203 KiB

Open AccessReview

Genetic Overlap between General Cognitive Function and Schizophrenia: A Review of Cognitive GWASs

by Kazutaka Ohi, Chika Sumiyoshi, Haruo Fujino, Yuka Yasuda, Hidenaga Yamamori, Michiko Fujimoto, Tomoko Shiino, Tomiki Sumiyoshi and Ryota Hashimoto

Int. J. Mol. Sci. 2018, 19(12), 3822; https://doi.org/10.3390/ijms19123822 - 30 Nov 2018

Cited by 47 | Viewed by 5679

Abstract

General cognitive (intelligence) function is substantially heritable, and is a major determinant of economic and health-related life outcomes. Cognitive impairments and intelligence decline are core features of schizophrenia which are evident before the onset of the illness. Genetic overlaps between cognitive impairments and [...] Read more.

General cognitive (intelligence) function is substantially heritable, and is a major determinant of economic and health-related life outcomes. Cognitive impairments and intelligence decline are core features of schizophrenia which are evident before the onset of the illness. Genetic overlaps between cognitive impairments and the vulnerability for the illness have been suggested. Here, we review the literature on recent large-scale genome-wide association studies (GWASs) of general cognitive function and correlations between cognitive function and genetic susceptibility to schizophrenia. In the last decade, large-scale GWASs (n > 30,000) of general cognitive function and schizophrenia have demonstrated that substantial proportions of the heritability of the cognitive function and schizophrenia are explained by a polygenic component consisting of many common genetic variants with small effects. To date, GWASs have identified more than 100 loci linked to general cognitive function and 108 loci linked to schizophrenia. These genetic variants are mostly intronic or intergenic. Genes identified around these genetic variants are densely expressed in brain tissues. Schizophrenia-related genetic risks are consistently correlated with lower general cognitive function (r_g = −0.20) and higher educational attainment (r_g = 0.08). Cognitive functions are associated with many of the socioeconomic and health-related outcomes. Current treatment strategies largely fail to improve cognitive impairments of schizophrenia. Therefore, further study is needed to understand the molecular mechanisms underlying both cognition and schizophrenia. Full article

(This article belongs to the Special Issue Molecular Psychiatry)

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20 pages, 446 KiB

Open AccessReview

Alterations of Expression of the Serotonin 5-HT4 Receptor in Brain Disorders

by Heike Rebholz, Eitan Friedman and Julia Castello

Int. J. Mol. Sci. 2018, 19(11), 3581; https://doi.org/10.3390/ijms19113581 - 13 Nov 2018

Cited by 49 | Viewed by 6919

Abstract

The serotonin 4 receptor, 5-HT₄R, represents one of seven different serotonin receptor families and is implicated in a variety of physiological functions and their pathophysiological variants, such as mood and depression or anxiety, food intake and obesity or anorexia, or memory [...] Read more.

The serotonin 4 receptor, 5-HT₄R, represents one of seven different serotonin receptor families and is implicated in a variety of physiological functions and their pathophysiological variants, such as mood and depression or anxiety, food intake and obesity or anorexia, or memory and memory loss in Alzheimer’s disease. Its central nervous system expression pattern in the forebrain, in particular in caudate putamen, the hippocampus and to lesser extent in the cortex, predispose it for a role in executive function and reward-related actions. In rodents, regional overexpression or knockdown in the prefrontal cortex or the nucleus accumbens of 5-HT₄R was shown to impact mood and depression-like phenotypes, food intake and hypophagia; however, whether expression changes are causally involved in the etiology of such disorders is not clear. In this context, more data are emerging, especially based on PET technology and the use of ligand tracers that demonstrate altered 5-HT₄R expression in brain disorders in humans, confirming data stemming from post-mortem tissue and preclinical animal models. In this review, we would like to present the current knowledge of 5-HT₄R expression in brain regions relevant to mood/depression, reward and executive function with a focus on 5-HT₄R expression changes in brain disorders or caused by drug treatment, at both the transcript and protein levels. Full article

(This article belongs to the Special Issue Molecular Psychiatry)

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30 pages, 6144 KiB

Open AccessReview

Multi-Target Approach for Drug Discovery against Schizophrenia

by Magda Kondej, Piotr Stępnicki and Agnieszka A. Kaczor

Int. J. Mol. Sci. 2018, 19(10), 3105; https://doi.org/10.3390/ijms19103105 - 10 Oct 2018

Cited by 66 | Viewed by 10666

Abstract

Polypharmacology is nowadays considered an increasingly crucial aspect in discovering new drugs as a number of original single-target drugs have been performing far behind expectations during the last ten years. In this scenario, multi-target drugs are a promising approach against polygenic diseases with [...] Read more.

Polypharmacology is nowadays considered an increasingly crucial aspect in discovering new drugs as a number of original single-target drugs have been performing far behind expectations during the last ten years. In this scenario, multi-target drugs are a promising approach against polygenic diseases with complex pathomechanisms such as schizophrenia. Indeed, second generation or atypical antipsychotics target a number of aminergic G protein-coupled receptors (GPCRs) simultaneously. Novel strategies in drug design and discovery against schizophrenia focus on targets beyond the dopaminergic hypothesis of the disease and even beyond the monoamine GPCRs. In particular these approaches concern proteins involved in glutamatergic and cholinergic neurotransmission, challenging the concept of antipsychotic activity without dopamine D₂ receptor involvement. Potentially interesting compounds include ligands interacting with glycine modulatory binding pocket on N-methyl-d-aspartate (NMDA) receptors, positive allosteric modulators of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, positive allosteric modulators of metabotropic glutamatergic receptors, agonists and positive allosteric modulators of α7 nicotinic receptors, as well as muscarinic receptor agonists. In this review we discuss classical and novel drug targets for schizophrenia, cover benefits and limitations of current strategies to design multi-target drugs and show examples of multi-target ligands as antipsychotics, including marketed drugs, substances in clinical trials, and other investigational compounds. Full article

(This article belongs to the Special Issue Molecular Psychiatry)

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Graphical abstract

19 pages, 797 KiB

Open AccessReview

DNA Methylation as a Biomarker of Treatment Response Variability in Serious Mental Illnesses: A Systematic Review Focused on Bipolar Disorder, Schizophrenia, and Major Depressive Disorder

by Charanraj Goud Alladi, Bruno Etain, Frank Bellivier and Cynthia Marie-Claire

Int. J. Mol. Sci. 2018, 19(10), 3026; https://doi.org/10.3390/ijms19103026 - 4 Oct 2018

Cited by 44 | Viewed by 6778

Abstract

So far, genetic studies of treatment response in schizophrenia, bipolar disorder, and major depression have returned results with limited clinical utility. A gene × environment interplay has been proposed as a factor influencing not only pathophysiology but also the treatment response. Therefore, epigenetics [...] Read more.

So far, genetic studies of treatment response in schizophrenia, bipolar disorder, and major depression have returned results with limited clinical utility. A gene × environment interplay has been proposed as a factor influencing not only pathophysiology but also the treatment response. Therefore, epigenetics has emerged as a major field of research to study the treatment of these three disorders. Among the epigenetic marks that can modify gene expression, DNA methylation is the best studied. We performed a systematic search (PubMed) following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA guidelines for preclinical and clinical studies focused on genome-wide and gene-specific DNA methylation in the context of schizophrenia, bipolar disorders, and major depressive disorder. Out of the 112 studies initially identified, we selected 31 studies among them, with an emphasis on responses to the gold standard treatments in each disorder. Modulations of DNA methylation levels at specific CpG sites have been documented for all classes of treatments (antipsychotics, mood stabilizers, and antidepressants). The heterogeneity of the models and methodologies used complicate the interpretation of results. Although few studies in each disorder have assessed the potential of DNA methylation as biomarkers of treatment response, data support this hypothesis for antipsychotics, mood stabilizers and antidepressants. Full article

(This article belongs to the Special Issue Molecular Psychiatry)

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