International Journal of Molecular Sciences

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3 pages, 185 KiB

Open AccessEditorial

Molecular Research on Mental Disorders

by Magdalena Sowa-Kućma and Katarzyna Stachowicz

Int. J. Mol. Sci. 2023, 24(8), 7104; https://doi.org/10.3390/ijms24087104 - 12 Apr 2023

Cited by 1 | Viewed by 946

Abstract

Mental disorders and substance use disorders affect approximately 13% of the world’s population [...] Full article

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

Research

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26 pages, 7335 KiB

Open AccessArticle

HERV-W ENV Induces Innate Immune Activation and Neuronal Apoptosis via linc01930/cGAS Axis in Recent-Onset Schizophrenia

by Xuhang Li, Xiulin Wu, Wenshi Li, Qiujin Yan, Ping Zhou, Yaru Xia, Wei Yao and Fan Zhu

Int. J. Mol. Sci. 2023, 24(3), 3000; https://doi.org/10.3390/ijms24033000 - 3 Feb 2023

Cited by 11 | Viewed by 2545

Abstract

Schizophrenia is a severe neuropsychiatric disorder affecting about 1% of individuals worldwide. Increased innate immune activation and neuronal apoptosis are common findings in schizophrenia. Interferon beta (IFN-β), an essential cytokine in promoting and regulating innate immune responses, causes neuronal apoptosis in vitro. However, [...] Read more.

Schizophrenia is a severe neuropsychiatric disorder affecting about 1% of individuals worldwide. Increased innate immune activation and neuronal apoptosis are common findings in schizophrenia. Interferon beta (IFN-β), an essential cytokine in promoting and regulating innate immune responses, causes neuronal apoptosis in vitro. However, the precise pathogenesis of schizophrenia is unknown. Recent studies indicate that a domesticated endogenous retroviral envelope glycoprotein of the W family (HERV-W ENV, also called ERVWE1 or syncytin 1), derived from the endogenous retrovirus group W member 1 (ERVWE1) locus on chromosome 7q21.2, has a high level in schizophrenia. Here, we found an increased serum IFN-β level in schizophrenia and showed a positive correlation with HERV-W ENV. In addition, serum long intergenic non-protein coding RNA 1930 (linc01930), decreased in schizophrenia, was negatively correlated with HERV-W ENV and IFN-β. In vitro experiments showed that linc01930, mainly in the nucleus and with noncoding functions, was repressed by HERV-W ENV through promoter activity suppression. Further studies indicated that HERV-W ENV increased IFN-β expression and neuronal apoptosis by restraining the expression of linc01930. Furthermore, HERV-W ENV enhanced cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes protein (STING) expression and interferon regulatory factor 3 (IRF3) phosphorylation in neuronal cells. Notably, cGAS interacted with HERV-W ENV and triggered IFN-β expression and neuronal apoptosis caused by HERV-W ENV. Moreover, Linc01930 participated in the increased neuronal apoptosis and expression level of cGAS and IFN-β induced by HERV-W ENV. To summarize, our results suggested that linc01930 and IFN-β might be novel potential blood-based biomarkers in schizophrenia. The totality of these results also showed that HERV-W ENV facilitated antiviral innate immune response, resulting in neuronal apoptosis through the linc01930/cGAS/STING pathway in schizophrenia. Due to its monoclonal antibody GNbAC1 application in clinical trials, we considered HERV-W ENV might be a reliable therapeutic choice for schizophrenia. Full article

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

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17 pages, 1219 KiB

Open AccessArticle

Antipsychotic- and Anxiolytic-like Properties of a Multimodal Compound JJGW08 in Rodents

by Elżbieta Żmudzka, Klaudia Lustyk, Monika Głuch-Lutwin, Barbara Mordyl, Alicja Zakrzewska-Sito, Paweł Mierzejewski, Jolanta Jaśkowska, Marcin Kołaczkowski, Jacek Sapa and Karolina Pytka

Int. J. Mol. Sci. 2022, 23(24), 15929; https://doi.org/10.3390/ijms232415929 - 14 Dec 2022

Cited by 3 | Viewed by 1394

Abstract

Schizophrenia is a chronic mental illness, which remains difficult to treat. A high resistance to the available therapies, their insufficient efficacy, and numerous side effects are the reasons why there is an urgent need to develop new antipsychotics. This study aimed to assess [...] Read more.

Schizophrenia is a chronic mental illness, which remains difficult to treat. A high resistance to the available therapies, their insufficient efficacy, and numerous side effects are the reasons why there is an urgent need to develop new antipsychotics. This study aimed to assess the antipsychotic-like effects of JJGW08, a novel arylpiperazine alkyl derivative of salicylamide, in rodents. First, considering the JJGW08 receptor profile, we investigated the compound’s intrinsic activity towards dopamine D₂ and serotonin 5-HT_1A, 5-HT_2A, and 5-HT₇ receptors using functional assays. Next, we assessed the effect of JJGW08 on MK-801- and amphetamine-induced hyperlocomotion, its risk of inducing catalepsy and impairing motor coordination, as well as the anxiolytic-like effects in the four-plate and marble burying tests in mice. Finally, we investigated the antipsychotic-like properties of JJGW08 in rats using MK-801-induced hyperlocomotion and prepulse inhibition tests. We found that JJGW08 showed antagonistic properties at dopamine D₂ and serotonin 5-HT_1A, 5-HT_2A, and 5-HT₇ receptors. However, the effect on the 5-HT_2A and 5-HT₇ receptors was very weak. Moreover, the tested compound showed an antipsychotic-like effect in MK-801- and amphetamine-induced hyperlocomotion but not in a prepulse inhibition test in rats. Notably, JJGW08 demonstrated anxiolytic-like properties in both behavioral tests. Importantly, the compound did not induce catalepsy or motor coordination impairment in mice at antipsychotic-like doses. Our study suggests it is worth searching for new potential antipsychotics among arylpiperazine alkyl derivatives of salicylamide. Full article

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

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15 pages, 1684 KiB

Open AccessArticle

Cocaine and Its Abstinence Condition Modulate Striatal and Hippocampal Wnt Signaling in a Male Rat Model of Drug Self-Administration

by Dawid Gawliński, Kinga Gawlińska, Małgorzata Frankowska and Małgorzata Filip

Int. J. Mol. Sci. 2022, 23(22), 14011; https://doi.org/10.3390/ijms232214011 - 13 Nov 2022

Cited by 2 | Viewed by 1756

Abstract

Recent years have provided more and more evidence confirming the important role of Wnt/β-catenin signaling in the pathophysiology of mental illnesses, including cocaine use disorder. High relapse rates, which is a hallmark of drug addiction, prompt the study of changes in Wnt signaling [...] Read more.

Recent years have provided more and more evidence confirming the important role of Wnt/β-catenin signaling in the pathophysiology of mental illnesses, including cocaine use disorder. High relapse rates, which is a hallmark of drug addiction, prompt the study of changes in Wnt signaling elements (Wnt5a, Wnt7b, and Ctnnb1) in the motivational aspects of cocaine use and early drug-free period (3 days after the last exposure to cocaine). For this purpose, an animal model of intravenous cocaine self-administration and two types of drug-free period (extinction training and abstinence in the home cage) were used. The studies showed that chronic cocaine self-administration mainly disturbs the expression of Wnt5a and Ctnnb1 (the gene encoding β-catenin) in the examined brain structures (striatum and hippocampus), and the examined types of early abstinence are characterized by a different pattern of changes in the expression of these genes. At the same time, in cocaine self-administrated animals, there were no changes in the level of Wnt5a and β-catenin proteins at the tested time points. Moreover, exposure to cocaine induces a significant reduction in the striatal and hippocampal expression of miR-374 and miR-544, which can regulate Wnt5a levels post-transcriptionally. In summary, previous observations from experimenter-administered cocaine have not been fully validated in the cocaine self-administration model. Yoked cocaine administration appears to disrupt Wnt signaling more than cocaine self-administration. The condition of the cocaine-free period, the routes of drug administration, and the motivational aspect of drug administration play an important role in the type of drug-induced molecular changes observed. Furthermore, in-depth research involving additional brain regions is needed to determine the exact role of Wnt signaling in short-term and long-lasting plasticity as well as in the motivational aspects of cocaine use, and thus to assess its potential as a target for new drug therapy for cocaine use disorder. Full article

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

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11 pages, 1669 KiB

Open AccessArticle

Glucocorticoid-Regulated Kinase CAMKIγ in the Central Amygdala Controls Anxiety-like Behavior in Mice

by Marcin Piechota, Urszula Skupio, Małgorzata Borczyk, Barbara Ziółkowska, Sławomir Gołda, Łukasz Szumiec, Klaudia Szklarczyk-Smolana, Wiktor Bilecki, Jan Manuel Rodriguez Parkitna and Michał Korostyński

Int. J. Mol. Sci. 2022, 23(20), 12328; https://doi.org/10.3390/ijms232012328 - 14 Oct 2022

Cited by 2 | Viewed by 2392

Abstract

The expression of the Calcium/Calmodulin-Dependent Protein Kinase I gamma (encoded by the Camk1g gene) depends on the activation of glucocorticoid receptors (GR) and is strongly regulated by stress. Since Camk1g is primarily expressed in neuronal cells of the limbic system in the brain, [...] Read more.

The expression of the Calcium/Calmodulin-Dependent Protein Kinase I gamma (encoded by the Camk1g gene) depends on the activation of glucocorticoid receptors (GR) and is strongly regulated by stress. Since Camk1g is primarily expressed in neuronal cells of the limbic system in the brain, we hypothesized that it could be involved in signaling mechanisms that underlie the adaptive or maladaptive responses to stress. Here, we find that restraint-induced stress and the GR agonist dexamethasone robustly increase the expression of Camk1g in neurons of the amygdalar nuclei in the mouse brain. To assess the functional role of Camk1g expression, we performed a virally induced knock-down of the transcript. Mice with bilateral amygdala-specific Camk1g knock-down showed increased anxiety-like behaviors in the light-dark box, and an increase in freezing behavior after fear-conditioning, but normal spatial working memory during exploration of a Y-maze. Thus, we confirm that Camk1g is a neuron-specific GR-regulated transcript, and show that it is specifically involved in behaviors related to anxiety, as well as responses conditioned by aversive stimuli. Full article

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

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Review

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44 pages, 2207 KiB

Open AccessReview

Pathophysiology and Current Drug Treatments for Post-Stroke Depression: A Review

by Dmitry Frank, Benjamin F. Gruenbaum, Alexander Zlotnik, Michael Semyonov, Amit Frenkel and Matthew Boyko

Int. J. Mol. Sci. 2022, 23(23), 15114; https://doi.org/10.3390/ijms232315114 - 1 Dec 2022

Cited by 25 | Viewed by 5448

Abstract

Post-stroke depression (PSD) is a biopsychosocial disorder that affects individuals who have suffered a stroke at any point. PSD has a 20 to 60 percent reported prevalence among stroke survivors. Its effects are usually adverse, can lead to disability, and may increase mortality [...] Read more.

Post-stroke depression (PSD) is a biopsychosocial disorder that affects individuals who have suffered a stroke at any point. PSD has a 20 to 60 percent reported prevalence among stroke survivors. Its effects are usually adverse, can lead to disability, and may increase mortality if not managed or treated early. PSD is linked to several other medical conditions, including anxiety, hyper-locomotor activity, and poor functional recovery. Despite significant awareness of its adverse impacts, understanding the pathogenesis of PSD has proved challenging. The exact pathophysiology of PSD is unknown, yet its complexity has been definitively shown, involving mechanisms such as dysfunction of monoamine, the glutamatergic systems, the gut-brain axis, and neuroinflammation. The current effectiveness of PSD treatment is about 30–40 percent of all cases. In this review, we examined different pathophysiological mechanisms and current pharmacological and non-pharmacological approaches for the treatment of PSD. Full article

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

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42 pages, 1234 KiB

Open AccessReview

Postsynaptic Proteins at Excitatory Synapses in the Brain—Relationship with Depressive Disorders

by Sylwia Samojedny, Ewelina Czechowska, Patrycja Pańczyszyn-Trzewik and Magdalena Sowa-Kućma

Int. J. Mol. Sci. 2022, 23(19), 11423; https://doi.org/10.3390/ijms231911423 - 28 Sep 2022

Cited by 8 | Viewed by 3034

Abstract

Depressive disorders (DDs) are an increasingly common health problem that affects all age groups. DDs pathogenesis is multifactorial. However, it was proven that stress is one of the most important environmental factors contributing to the development of these conditions. In recent years, there [...] Read more.

Depressive disorders (DDs) are an increasingly common health problem that affects all age groups. DDs pathogenesis is multifactorial. However, it was proven that stress is one of the most important environmental factors contributing to the development of these conditions. In recent years, there has been growing interest in the role of the glutamatergic system in the context of pharmacotherapy of DDs. Thus, it has become increasingly important to explore the functioning of excitatory synapses in pathogenesis and pharmacological treatment of psychiatric disorders (including DDs). This knowledge may lead to the description of new mechanisms of depression and indicate new potential targets for the pharmacotherapy of illness. An excitatory synapse is a highly complex and very dynamic structure, containing a vast number of proteins. This review aimed to discuss in detail the role of the key postsynaptic proteins (e.g., NMDAR, AMPAR, mGluR5, PSD-95, Homer, NOS etc.) in the excitatory synapse and to systematize the knowledge about changes that occur in the clinical course of depression and after antidepressant treatment. In addition, a discussion on the potential use of ligands and/or modulators of postsynaptic proteins at the excitatory synapse has been presented. Full article

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

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32 pages, 924 KiB

Open AccessReview

Crosstalk between Schizophrenia and Metabolic Syndrome: The Role of Oxytocinergic Dysfunction

by Kah Kheng Goh, Cynthia Yi-An Chen, Tzu-Hua Wu, Chun-Hsin Chen and Mong-Liang Lu

Int. J. Mol. Sci. 2022, 23(13), 7092; https://doi.org/10.3390/ijms23137092 - 25 Jun 2022

Cited by 11 | Viewed by 6520

Abstract

The high prevalence of metabolic syndrome in persons with schizophrenia has spurred investigational efforts to study the mechanism beneath its pathophysiology. Early psychosis dysfunction is present across multiple organ systems. On this account, schizophrenia may be a multisystem disorder in which one organ [...] Read more.

The high prevalence of metabolic syndrome in persons with schizophrenia has spurred investigational efforts to study the mechanism beneath its pathophysiology. Early psychosis dysfunction is present across multiple organ systems. On this account, schizophrenia may be a multisystem disorder in which one organ system is predominantly affected and where other organ systems are also concurrently involved. Growing evidence of the overlapping neurobiological profiles of metabolic risk factors and psychiatric symptoms, such as an association with cognitive dysfunction, altered autonomic nervous system regulation, desynchrony in the resting-state default mode network, and shared genetic liability, suggest that metabolic syndrome and schizophrenia are connected via common pathways that are central to schizophrenia pathogenesis, which may be underpinned by oxytocin system dysfunction. Oxytocin, a hormone that involves in the mechanisms of food intake and metabolic homeostasis, may partly explain this piece of the puzzle in the mechanism underlying this association. Given its prosocial and anorexigenic properties, oxytocin has been administered intranasally to investigate its therapeutic potential in schizophrenia and obesity. Although the pathophysiology and mechanisms of oxytocinergic dysfunction in metabolic syndrome and schizophrenia are both complex and it is still too early to draw a conclusion upon, oxytocinergic dysfunction may yield a new mechanistic insight into schizophrenia pathogenesis and treatment. Full article

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

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32 pages, 931 KiB

Open AccessReview

Advantages and Limitations of Animal Schizophrenia Models

by Magdalena Białoń and Agnieszka Wąsik

Int. J. Mol. Sci. 2022, 23(11), 5968; https://doi.org/10.3390/ijms23115968 - 25 May 2022

Cited by 37 | Viewed by 11727

Abstract

Mental illness modeling is still a major challenge for scientists. Animal models of schizophrenia are essential to gain a better understanding of the disease etiopathology and mechanism of action of currently used antipsychotic drugs and help in the search for new and more [...] Read more.

Mental illness modeling is still a major challenge for scientists. Animal models of schizophrenia are essential to gain a better understanding of the disease etiopathology and mechanism of action of currently used antipsychotic drugs and help in the search for new and more effective therapies. We can distinguish among pharmacological, genetic, and neurodevelopmental models offering various neuroanatomical disorders and a different spectrum of symptoms of schizophrenia. Modeling schizophrenia is based on inducing damage or changes in the activity of relevant regions in the rodent brain (mainly the prefrontal cortex and hippocampus). Such artificially induced dysfunctions approximately correspond to the lesions found in patients with schizophrenia. However, notably, animal models of mental illness have numerous limitations and never fully reflect the disease state observed in humans. Full article

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

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