RESUMO
Schizophrenia (SCZ) is a severe psychiatric disorder with unclear pathophysiology. Moreover, there is no specific biological marker to help clinicians to define a diagnosis, and medication is decided according to the psychiatrist's experience. In this scenario, microRNAs (miRNAs), which are small noncoding RNA molecules that regulate several genes, emerge as potential peripheral biomarkers to help not only the evaluation of the disease state but also the treatment response. Here, we systematically reviewed indexed literature and evaluated follow-up studies investigating the changes in miRNA expression due to antipsychotic treatment. We also assessed target genes and performed pathway enrichment analysis of miRNAs listed in this systematic review. A total of 11 studies were selected according to research criteria, and we observed that 28 miRNAs play a relevant role in schizophrenia pathogenesis or response to antipsychotic treatment, seven of those of extreme interest as possible biomarkers either for condition or treatment. Predicted targets of the miRNAs reviewed here were previously associated with schizophrenia in genome-wide studies, and pathway analysis showed enrichment for genes related to neural processes. With this review, we expect to highlight the importance of miRNAs in schizophrenia pathogenesis and its treatment and point out interesting miRNAs to future studies.
Assuntos
Antipsicóticos , MicroRNAs , Esquizofrenia , Humanos , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , MicroRNAs/genética , Antipsicóticos/farmacologiaRESUMO
Here, we explored the impact of prolonged environmental enrichment (EE) on behavioral, neurochemical, and epigenetic changes in the serotonin transporter gene in mice subjected to a two-hit schizophrenia model. The methodology involved administering the viral mimetic PolyI:C to neonatal Swiss mice as a first hit during postnatal days (PND) 5-7, or a sterile saline solution as a control. At PND21, mice were randomly assigned either to standard environment (SE) or EE housing conditions. Between PND35-44, the PolyI:C-treated group was submitted to various unpredictable stressors, constituting the second hit. Behavioral assessments were conducted on PND70, immediately after the final EE exposure. Following the completion of behavioral assessments, we evaluated the expression of proteins in the hippocampus that are indicative of microglial activation, such as Iba-1, as well as related to neurogenesis, including doublecortin (Dcx). We also performed methylation analysis on the serotonin transporter gene (Slc6a4) to investigate alterations in serotonin signaling. The findings revealed that EE for 50 days mitigated sensorimotor gating deficits and working memory impairments in two-hit mice and enhanced their locomotor and exploratory behaviors. EE also normalized the overexpression of hippocampal Iba-1 and increased the expression of hippocampal Dcx. Additionally, we observed hippocampal demethylation of the Slc6a4 gene in the EE-exposed two-hit group, indicating epigenetic reprogramming. These results contribute to the growing body of evidence supporting the protective effects of long-term EE in counteracting behavioral disruptions caused by the two-hit schizophrenia model, pointing to enhanced neurogenesis, diminished microglial activation, and epigenetic modifications of serotonergic pathways as underlying mechanisms.
Assuntos
Modelos Animais de Doenças , Meio Ambiente , Hipocampo , Esquizofrenia , Proteínas da Membrana Plasmática de Transporte de Serotonina , Animais , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Hipocampo/metabolismo , Esquizofrenia/metabolismo , Esquizofrenia/genética , Camundongos , Masculino , Proteína Duplacortina , Regiões Promotoras Genéticas , Metilação de DNA , Poli I-C , Neurogênese/fisiologia , Filtro Sensorial/fisiologiaRESUMO
OBJECTIVE: The advancement of neuroimaging and genetic research has revealed the presence of morphological abnormalities and numerous risk genes, along with their associations. We aimed to estimate magnetic resonance imaging-derived cortical thickness across multiple brain regions. METHODS: The cortical thickness of 129 schizophrenia patients, 42 of their unaffected siblings, and 112 healthy controls was measured and the candidate genes were sequenced. Comparisons were made of cortical thickness (including 68 regions of the Desikan-Killiany Atlas) and genetic variants (in 108 risk genes for schizophrenia) among the three groups, and correlation analyses were performed regarding cortical thickness, clinical symptoms, cognitive tests (such as the N-back task and the logical memory test), and genetic variants. RESULTS: Schizophrenia patients had significantly thinner bilateral frontal, temporal, and parietal gyri than healthy controls and unaffected siblings. Association analyses in target genes showed that four single nucleotide variants (SNVs) were significantly associated with schizophrenia, including thioredoxin-related transmembrane protein 2-catenin, cadherin-associated protein, delta 1 (SNV20673) (positive false discovery rate [PFDR] = 0.008) and centromere protein M (rs35542507, rs41277477, rs73165153) (PFDR = 0.030). Additionally, cortical thickness in the right pars triangularis was lower in carriers of the SNV20673 variant than in non-carriers (PFDR = 0.048). Finally, a positive correlation was found between right pars triangularis cortical thickness and logical memory in schizophrenia patients (r = 0.199, p = 0.032). CONCLUSIONS: This study identified regional morphological abnormalities in schizophrenia, including the right homologue of Broca's area, which was associated with a risk variant that affected delta-1 catenin and logical memory. These findings suggest a potential association between candidate gene loci, cortical thickness, and schizophrenia.
Assuntos
Imageamento por Ressonância Magnética , Polimorfismo de Nucleotídeo Único , Esquizofrenia , Irmãos , Humanos , Esquizofrenia/genética , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/patologia , Masculino , Feminino , Adulto , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Predisposição Genética para Doença/genética , delta Catenina , Cateninas/genética , Espessura Cortical do Cérebro , Adulto Jovem , Córtex Cerebral/patologia , Córtex Cerebral/diagnóstico por imagem , Proteínas de Membrana/genética , Pessoa de Meia-Idade , GenótipoRESUMO
BACKGROUND: Consistent with postmortem findings in patients, most animal models for schizophrenia (SCZ) present abnormal levels of parvalbumin (PV), a marker of fast-spiking GABAergic interneurons, in the prefrontal cortex (PFC) and hippocampus (HIP). However, there are discrepancies in the literature. PV reductions lead to a functional loss of PV interneurons, which is proposed to underly SCZ symptoms. Given its complex etiology, different categories of animal models have been developed to study SCZ, which may distinctly impact PV levels in rodent brain areas. STUDY DESIGN: We performed a quantitative meta-analysis on PV-positive cell number/density and expression levels in the PFC and HIP of animal models for SCZ based on pharmacological, neurodevelopmental, and genetic manipulations. RESULTS: Our results confirmed that PV levels are significantly reduced in the PFC and HIP regardless of the animal model. By categorizing into subgroups, we found that all pharmacological models based on NMDA receptor antagonism decreased PV-positive cell number/density or PV expression levels in both brain areas examined. In neurodevelopmental models, abnormal PV levels were confirmed in both brain areas in maternal immune activation models and HIP of the methylazoxymethanol acetate model. In genetic models, negative effects were found in neuregulin 1 and ERBB4 mutant mice in both brain regions and the PFC of dysbindin mutant mice. Regarding sex differences, male rodents exhibited PV reductions in both brain regions only in pharmacological models, while few studies have been conducted in females. CONCLUSION: Overall, our findings support deficits in prefrontal and hippocampal PV interneurons in animal models for SCZ.
Assuntos
Esquizofrenia , Humanos , Camundongos , Masculino , Feminino , Animais , Esquizofrenia/genética , Parvalbuminas/metabolismo , Modelos Animais de Doenças , Interneurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Hipocampo/metabolismoRESUMO
Schizophrenia (SZ) is a multifactorial disorder characterized by volume reduction in gray and white matter, oxidative stress, neuroinflammation, altered neurotransmission, as well as molecular deficiencies such as punctual mutation in DisruptedinSchizophrenia 1 protein. In this regard, it is essential to understand the underlying molecular disturbances to determine the pathophysiological mechanisms of the disease. The signaling pathways activated by G proteincoupled receptors (GPCRs) are key molecular signaling pathways altered in SZ. Convenient models need to be designed and validated to study these processes and mechanisms at the cellular level. Cultured olfactory stem cells are used to investigate neural molecular and cellular alterations related to the pathophysiology of SZ. Multipotent human olfactory stem cells are undifferentiated and express GPCRs involved in numerous physiological functions such as proliferation, differentiation and bioenergetics. The use of olfactory stem cells obtained from patients with SZ may identify alterations in GPCR signaling that underlie dysfunctional processes in both undifferentiated and specialized neurons or derived neuroglia. The present review aimed to analyze the role of GPCRs and their signaling in the pathophysiology of SZ. Culture of olfactory epithelial cells constitutes a suitable model to study SZ and other psychiatric disorders at the cellular level.
Assuntos
Esquizofrenia , Humanos , Esquizofrenia/genética , Esquizofrenia/metabolismo , Células Neuroepiteliais/metabolismo , Neurônios/metabolismo , Receptores Acoplados a Proteínas G , Células-Tronco/metabolismoRESUMO
This study aimed to evaluate Haloperidol's (Hal) effects on the behavioral, neurotrophic factors, and epigenetic parameters in an animal model of schizophrenia (SCZ) induced by ketamine (Ket). Injections of Ket or saline were administered intraperitoneal (once a day) between the 1st and 14th days of the experiment. Water or Hal was administered via gavage between the 8th and 14th experimental days. Thirty minutes after the last injection, the animals were subjected to behavioral analysis. The activity of DNA methyltransferase (DNMT), histone deacetylase (HDAC), and histone acetyltransferase and levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and glial-derived neurotrophic factor (GDNF) were evaluated in the frontal cortex, hippocampus, and striatum. Ket increased the covered distance and time spent in the central area of the open field, and Hal did not reverse these behavioral alterations. Significant increases in the DNMT and HDAC activities were detected in the frontal cortex and striatum from rats that received Ket, Hal, or a combination thereof. Besides, Hal per se increased the activity of DNMT and HDAC in the hippocampus of rats. Hal per se or the association of Ket plus Hal decreased BDNF, NGF, NT-3, and GDNF, depending on the brain region and treatment regimen. The administration of Hal can alter the levels of neurotrophic factors and the activity of epigenetic enzymes, which can be a factor in the development of effect collateral in SCZ patients. However, the precise mechanisms involved in these alterations are still unclear.
Assuntos
Ketamina , Esquizofrenia , Humanos , Ratos , Animais , Haloperidol/farmacologia , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Ketamina/toxicidade , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial , Fator de Crescimento Neural/genética , Modelos Animais de Doenças , Epigênese GenéticaRESUMO
OBJECTIVES: This systematic review and meta-analysis focussed on insights into the relationship between CACNA1C-rs1006737 and ZNF804A-rs1344706 polymorphisms and cognitive performance in schizophrenia (SCZ) spectrum and bipolar disorder (BD) and provide some contributions for clinical practice. METHODS: We searched the websites databases (PubMED, PsycINFO, Web of Science, EMBASE and Cochrane Library) using eligibility and exclusion criteria to capture all potential studies, based on PICO model and according to the PRISMA. RESULTS: Eight articles were included in this systematic review (five referring to CACNA1C-rs1006737 and three related to ZNF804A-rs1344706 polymorphisms), with a total of 5759 participants (1751 SCZ patients, 348 BD patients, 3626 controls and 34 first-degree relatives). The results demonstrated that the pooled effect of CACNA1C-rs1006737 (risk difference RD = 0.08; 95% CI 0.02-0.15) was associated with altered cognitive function in patients with severe mental disorders, but not ZNF804A-rs1344706 polymorphism (RD = 0.19; 95% CI 0.09-0.48. CONCLUSION: The present meta-analysis provides evidence regarding slight association between CACNA1C-rs1006737 polymorphisms and cognitive performance in severe mental disorders, indicating that cognitive impairment in severe mental disorders associated with the CACNA1C rs1006737 risk variants could only be expressed when interacting with environmental exposures. This study is registered with PROSPERO, number CRD42021246726.
Assuntos
Predisposição Genética para Doença , Esquizofrenia , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição Kruppel-Like/genética , Esquizofrenia/genética , Cognição , Canais de Cálcio Tipo L/genéticaRESUMO
One of the challenges in studying neuropsychiatric disorders is the difficulty in accessing brain tissue from living patients. Schizophrenia is a chronic mental illness that affects 1% of the population worldwide, and its development stems from genetic and environmental factors. In order to better understand the pathophysiology underlying schizophrenia, the development of efficient in vitro methods to model this disorder has been required. In addition to several in vitro models, induced pluripotent stem cells (iPSCs) arose as a powerful tool, enabling access to the genetic background of the donor. Moreover, genetic modification of these cells can improve studies of specific dysfunctions observed in the pathophysiology of several neuropsychiatric disorders, not only schizophrenia. Here, we summarize which in vitro models are currently available and their applications in schizophrenia research, describing their advantages and limitations. These technologies in the cell culture field hold great potential to contribute to a better understanding of the pathophysiology of schizophrenia in an integrated manner, in addition to testing potential therapeutic interventions based on the genetic background of the patient.
Assuntos
Células-Tronco Pluripotentes Induzidas , Esquizofrenia , Encéfalo , Técnicas de Cultura de Células/métodos , Humanos , Neurônios , Esquizofrenia/genéticaRESUMO
Schizophrenia is an incurable mental disorder that affects 1% of the world population and is among the most disabling human diseases. On average, 70% of patients abandon medication due to its low efficacy and the presence of severe side effects. To change these conditions, it is necessary to understand the pathophysiology of schizophrenia at the molecular level. Besides the long-established neurodevelopmental hypothesis, works based on neuroimaging, postmortem brain proteomics, and pharmacological, genetic, and animal model studies have shown dysfunction and deficits in synaptic transmission. Currently, genetic editing has been growing, and the use of this technique has been improved in the discovery of protein functions; in addition to that, some recent studies have attributed a path to the use of genetic engineering in the treatment of diseases with a genetic nature.
Assuntos
Esquizofrenia , Animais , Encéfalo , Humanos , Neuroimagem , Proteômica , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Transmissão SinápticaRESUMO
Post-translational modifications (PTMs) of proteins occur in all domains of life, affecting various structural and functional properties. Multiple methods can be used to study PTMs depending on the biological question, which can vary widely. Schizophrenia is a widespread brain disorder that possesses many known contributing environmental factors and hundreds of genetic risk factors; however, a full picture of the mechanisms behind how and why this disorder occurs and how it can be treated remains unknown. Various PTMs have been found to be differentially expressed in several pathways that are dysregulated in schizophrenia, as seen in cell line and animal models, postmortem brain tissue from people with schizophrenia, and biological fluids like blood, plasma, and cerebrospinal fluid. Despite recent advances, several pathways have been completely left undisturbed by PTMomics and show great promise for better understanding of protein dynamics in schizophrenia, how the disease state occurs, and how it may be better treated in future therapies.