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Molecular Advances in Schizophrenia
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Molecular Advances in Schizophrenia

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: closed (31 July 2022) | Viewed by 14092

Special Issue Editor

Dr. Chieh-Hsin Lin

E-Mail
Guest Editor
Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
Interests: psychiatry; geriatric psychiatry; schizophrenia; dementia; NMDA; psychopharmacology

Special Issue Information

Dear Colleagues,

Schizophrenia is a chronic brain disorder characterized by positive symptoms (e.g., delusions and hallucinations), negative symptoms (e.g., apathy, lack of motivation, social withdrawal, etc.), cognitive deficits and functional deterioration. The pathogeneses of schizophrenia are still uncertain. Current antipsychotics that mainly target at dopaminergic antagonism or modulation have limited efficacy for the treatment of cognitive or functional impairment. Biomarkers for assisting the diagnosis of schizophrenia are also lacking. Currently the diagnosis of schizophrenia mainly relies on clinical assessment.

In addition to the dopamine hypothesis of schizophrenia, glutamate hypothesis, abnormalities in brain structure or brain network, abnormalities in the gut microbiota or immune dysfunction are under development. This Special Issue of IJMS explores the advances in the diagnosis and treatment of schizophrenia from the molecular aspect.

Dr. Chieh-Hsin Lin
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • schizophrenia
  • dopamine
  • glutamate
  • cognitive deficits
  • neurodevelopment
  • neurodegeneration
  • brain circuits
  • biomarkers of schizophrenia
  • gut microbiota

Published Papers (6 papers)

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Research

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16 pages, 1238 KiB  
Article
Insulin-like Growth Factor 2 (IGF-2) and Insulin-like Growth Factor Binding Protein 7 (IGFBP-7) Are Upregulated after Atypical Antipsychotics in Spanish Schizophrenia Patients
by Carlos Fernández-Pereira, Maria Aránzazu Penedo, Tania Rivera-Baltanas, Rafael Fernández-Martínez, Saida Ortolano, José Manuel Olivares and Roberto Carlos Agís-Balboa
Int. J. Mol. Sci. 2022, 23(17), 9591; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179591 - 24 Aug 2022
Cited by 3 | Viewed by 1953
Abstract
Insulin-like growth factor 2 (IGF-2) and IGF binding protein 7 (IGFBP-7) have been related to schizophrenia (SZ) due to their implication in neurodevelopment. The purpose of this study was to assess whether the alterations in IGF-2 and IGFBP-7 in SZ patients are intrinsically [...] Read more.
Insulin-like growth factor 2 (IGF-2) and IGF binding protein 7 (IGFBP-7) have been related to schizophrenia (SZ) due to their implication in neurodevelopment. The purpose of this study was to assess whether the alterations in IGF-2 and IGFBP-7 in SZ patients are intrinsically related to the psychiatric disorder itself or are a secondary phenomenon due to antipsychotic treatment. In order to test this hypothesis, we measured plasma IGF-2 and IGFBP-7 in drug-naïve first episode (FE) and multiple episodes or chronic (ME) SZ Caucasian patients who have been following treatment for years. A total of 55 SZ patients (FE = 15, ME = 40) and 45 healthy controls were recruited. The Positive and Negative Syndrome Scale (PANSS) and the Self-Assessment Anhedonia Scale (SAAS) were employed to check schizophrenic symptomatology and anhedonia, respectively. Plasma IGF-2 and IGFBP-7 levels were measured by Enzyme-Linked Immunosorbent Assay (ELISA). The FE SZ patients had much lower IGF-2, but not IGFBP-7, than controls. Moreover, both IGF-2 and IGFBP-7 significantly increased after atypical antipsychotic treatment (aripiprazole, olanzapine, or risperidone) in these patients. On the other hand, chronic patients showed higher levels of both proteins when compared to controls. Our study suggests that circulatory IGF-2 and IGFBP-7 increase after antipsychotic treatment, regardless of long-term conditions and being lower in drug-naïve FE patients. Full article
(This article belongs to the Special Issue Molecular Advances in Schizophrenia)
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15 pages, 1780 KiB  
Article
Chronic N-Acetylcysteine Treatment Prevents Amphetamine-Induced Hyperactivity in Heterozygous Disc1 Mutant Mice, a Putative Prodromal Schizophrenia Animal Model
by Chuan-Ching Lai, Rathinasamy Baskaran, Chih-Yu Tsao, Li-Heng Tuan, Pei-Fen Siow, Mahalakshmi Palani, Lukas Jyuhn-Hsiarn Lee, Chih-Min Liu, Hai-Gwo Hwu and Li-Jen Lee
Int. J. Mol. Sci. 2022, 23(16), 9419; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169419 - 20 Aug 2022
Cited by 2 | Viewed by 2542
Abstract
Symptoms of schizophrenia (SZ) typically emerge during adolescence to young adulthood, which gives a window before full-blown psychosis for early intervention. Strategies for preventing the conversion from the prodromal phase to the psychotic phase are warranted. Heterozygous (Het) Disc1 mutant mice are considered [...] Read more.
Symptoms of schizophrenia (SZ) typically emerge during adolescence to young adulthood, which gives a window before full-blown psychosis for early intervention. Strategies for preventing the conversion from the prodromal phase to the psychotic phase are warranted. Heterozygous (Het) Disc1 mutant mice are considered a prodromal model of SZ, suitable for studying psychotic conversion. We evaluated the preventive effect of chronic N-acetylcysteine (NAC) administration, covering the prenatal era to adulthood, on the reaction following the Amph challenge, which mimics the outbreak or conversion of psychosis, in adult Het Disc1 mice. Biochemical and morphological features were examined in the striatum of NAC-treated mice. Chronic NAC treatment normalized the Amph-induced activity in the Het Disc1 mice. Furthermore, the striatal phenotypes of Het Disc1 mice were rescued by NAC including dopamine receptors, the expression of GSK3s, MSN dendritic impairments, and striatal PV density. The current study demonstrated a potent preventive effect of chronic NAC treatment in Disc1 Het mice on the acute Amph test, which mimics the outbreak of psychosis. Our findings not only support the benefit of NAC as a dietary supplement for SZ prodromes, but also advance our knowledge of striatal dopamine receptors, PV neurons, and GSK3 signaling pathways as therapeutic targets for treating or preventing the pathogenesis of mental disorders. Full article
(This article belongs to the Special Issue Molecular Advances in Schizophrenia)
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12 pages, 1211 KiB  
Article
Caffeine-Induced Acute and Delayed Responses in Cerebral Metabolism of Control and Schizophrenia-like Wisket Rats
by Gyöngyi Horvath, István Kertész, Tamás Nagy, Leatitia Gabriella Adlan, Gabriella Kekesi, Alexandra Büki, Gabor Tuboly and György Trencsényi
Int. J. Mol. Sci. 2022, 23(15), 8186; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158186 - 25 Jul 2022
Cited by 2 | Viewed by 1374
Abstract
Recently, morphological impairments have been detected in the brain of a triple-hit rat schizophrenia model (Wisket), and delayed depressive effects of caffeine treatment in both control and Wisket animals have also been shown. The aims of this study were to determine the basal [...] Read more.
Recently, morphological impairments have been detected in the brain of a triple-hit rat schizophrenia model (Wisket), and delayed depressive effects of caffeine treatment in both control and Wisket animals have also been shown. The aims of this study were to determine the basal and caffeine-induced acute (30 min) and delayed (24 h) changes in the cerebral 18fluorodeoxyglucose (18F-FDG) uptake by positron emission tomography (PET) in control and Wisket rats. No significant differences were identified in the basal whole-brain metabolism between the two groups, and the metabolism was not modified acutely by a single intraperitoneal caffeine (20 mg/kg) injection in either group. However, one day after caffeine administration, significantly enhanced 18F-FDG uptake was detected in the whole brain and the investigated areas (hippocampus, striatum, thalamus, and hypothalamus) in the control group. Although the Wisket animals showed only moderate enhancements in the 18F-FDG uptake, significantly lower brain metabolism was observed in this group than in the caffeine-treated control group. This study highlights that the basal brain metabolism of Wisket animals was similar to control rats, and that was not influenced acutely by single caffeine treatment at the whole-brain level. Nevertheless, the distinct delayed responsiveness to this psychostimulant in Wisket model rats suggests impaired control of the cerebral metabolism. Full article
(This article belongs to the Special Issue Molecular Advances in Schizophrenia)
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12 pages, 2994 KiB  
Article
Effects of Psychotropic Drugs on Ribosomal Genes and Protein Synthesis
by Zoe S. J. Liu, Trang T. T. Truong, Chiara C. Bortolasci, Briana Spolding, Bruna Panizzutti, Courtney Swinton, Jee Hyun Kim, Srisaiyini Kidnapillai, Mark F. Richardson, Laura Gray, Olivia M. Dean, Sean L. McGee, Michael Berk and Ken Walder
Int. J. Mol. Sci. 2022, 23(13), 7180; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137180 - 28 Jun 2022
Cited by 8 | Viewed by 2057
Abstract
Altered protein synthesis has been implicated in the pathophysiology of several neuropsychiatric disorders, particularly schizophrenia. Ribosomes are the machinery responsible for protein synthesis. However, there remains little information on whether current psychotropic drugs affect ribosomes and contribute to their therapeutic effects. We treated [...] Read more.
Altered protein synthesis has been implicated in the pathophysiology of several neuropsychiatric disorders, particularly schizophrenia. Ribosomes are the machinery responsible for protein synthesis. However, there remains little information on whether current psychotropic drugs affect ribosomes and contribute to their therapeutic effects. We treated human neuronal-like (NT2-N) cells with amisulpride (10 µM), aripiprazole (0.1 µM), clozapine (10 µM), lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), risperidone (0.1 µM), valproate (0.5 mM) or vehicle control for 24 h. Transcriptomic and gene set enrichment analysis (GSEA) identified that the ribosomal pathway was altered by these drugs. We found that three of the eight drugs tested significantly decreased ribosomal gene expression, whilst one increased it. Most changes were observed in the components of cytosolic ribosomes and not mitochondrial ribosomes. Protein synthesis assays revealed that aripiprazole, clozapine and lithium all decreased protein synthesis. Several currently prescribed psychotropic drugs seem to impact ribosomal gene expression and protein synthesis. This suggests the possibility of using protein synthesis inhibitors as novel therapeutic agents for neuropsychiatric disorders. Full article
(This article belongs to the Special Issue Molecular Advances in Schizophrenia)
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17 pages, 3491 KiB  
Article
Receptor-Mediated AKT/PI3K Signalling and Behavioural Alterations in Zebrafish Larvae Reveal Association between Schizophrenia and Opioid Use Disorder
by Siroshini K. Thiagarajan, Siew Ying Mok, Satoshi Ogawa, Ishwar S. Parhar and Pek Yee Tang
Int. J. Mol. Sci. 2022, 23(9), 4715; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094715 - 25 Apr 2022
Cited by 3 | Viewed by 2543
Abstract
The link between substance abuse and the development of schizophrenia remains elusive. In this study, we assessed the molecular and behavioural alterations associated with schizophrenia, opioid addiction, and opioid withdrawal using zebrafish as a biological model. Larvae of 2 days post fertilization (dpf) [...] Read more.
The link between substance abuse and the development of schizophrenia remains elusive. In this study, we assessed the molecular and behavioural alterations associated with schizophrenia, opioid addiction, and opioid withdrawal using zebrafish as a biological model. Larvae of 2 days post fertilization (dpf) were exposed to domperidone (DMP), a dopamine-D2 dopamine D2 receptor antagonist, and morphine for 3 days and 10 days, respectively. MK801, an N-methyl-D-aspartate (NMDA) receptor antagonist, served as a positive control to mimic schizophrenia-like behaviour. The withdrawal syndrome was assessed 5 days after the termination of morphine treatment. The expressions of schizophrenia susceptibility genes, i.e., pi3k, akt1, slc6a4, creb1 and adamts2, in brains were quantified, and the levels of whole-body cyclic adenosine monophosphate (cAMP), serotonin and cortisol were measured. The aggressiveness of larvae was observed using the mirror biting test. After the short-term treatment with DMP and morphine, all studied genes were not differentially expressed. As for the long-term exposure, akt1 was downregulated by DMP and morphine. Downregulation of pi3k and slc6a4 was observed in the morphine-treated larvae, whereas creb1 and adamts2 were upregulated by DMP. The levels of cAMP and cortisol were elevated after 3 days, whereas significant increases were observed in all of the biochemical tests after 10 days. Compared to controls, increased aggression was observed in the DMP-, but not morphine-, treated group. These two groups showed reduction in aggressiveness when drug exposure was prolonged. Both the short- and long-term morphine withdrawal groups showed downregulation in all genes examined except creb1, suggesting dysregulated reward circuitry function. These results suggest that biochemical and behavioural alterations in schizophrenia-like symptoms and opioid dependence could be controlled by common mechanisms. Full article
(This article belongs to the Special Issue Molecular Advances in Schizophrenia)
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Review

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23 pages, 1609 KiB  
Review
Cytokine Imbalance as a Biomarker of Treatment-Resistant Schizophrenia
by Natalia A. Shnayder, Aiperi K. Khasanova, Anna I. Strelnik, Mustafa Al-Zamil, Andrey P. Otmakhov, Nikolay G. Neznanov, German A. Shipulin, Marina M. Petrova, Natalia P. Garganeeva and Regina F. Nasyrova
Int. J. Mol. Sci. 2022, 23(19), 11324; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911324 - 26 Sep 2022
Cited by 16 | Viewed by 2864
Abstract
Treatment-resistant schizophrenia (TRS) is an important and unresolved problem in biological and clinical psychiatry. Approximately 30% of cases of schizophrenia (Sch) are TRS, which may be due to the fact that some patients with TRS may suffer from pathogenetically “non-dopamine” Sch, in the [...] Read more.
Treatment-resistant schizophrenia (TRS) is an important and unresolved problem in biological and clinical psychiatry. Approximately 30% of cases of schizophrenia (Sch) are TRS, which may be due to the fact that some patients with TRS may suffer from pathogenetically “non-dopamine” Sch, in the development of which neuroinflammation is supposed to play an important role. The purpose of this narrative review is an attempt to summarize the data characterizing the patterns of production of pro-inflammatory and anti-inflammatory cytokines during the development of therapeutic resistance to APs and their pathogenetic and prognostic significance of cytokine imbalance as TRS biomarkers. This narrative review demonstrates that the problem of evaluating the contribution of pro-inflammatory and anti-inflammatory cytokines to maintaining or changing the cytokine balance can become a new key in unlocking the mystery of “non-dopamine” Sch and developing new therapeutic strategies for the treatment of TRS and psychosis in the setting of acute and chronic neuroinflammation. In addition, the inconsistency of the results of previous studies on the role of pro-inflammatory and anti-inflammatory cytokines indicates that the TRS biomarker, most likely, is not the serum level of one or more cytokines, but the cytokine balance. We have confirmed the hypothesis that cytokine imbalance is one of the most important TRS biomarkers. This hypothesis is partially supported by the variable response to immunomodulators in patients with TRS, which were prescribed without taking into account the cytokine balance of the relation between serum levels of the most important pro-inflammatory and anti-inflammatory cytokines for TRS. Full article
(This article belongs to the Special Issue Molecular Advances in Schizophrenia)
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