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1.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807989

RESUMO

For a better translation from treatment designs of schizophrenia to clinical efficiency, there is a crucial need to refine preclinical animal models. In order to consider the multifactorial nature of the disorder, a new mouse model associating three factors (genetic susceptibility-partial deletion of the MAP6 gene, early-life stress-maternal separation, and pharmacological treatment-chronic Δ-9-tetrahydrocannabinol during adolescence) has recently been described. While this model depicts a schizophrenia-like phenotype, the neurobiological correlates remain unknown. Synaptic transmission and functional plasticity of the CA1 hippocampal region of male and female 3-hit mice were therefore investigated using electrophysiological recordings on the hippocampus slice. While basal excitatory transmission remained unaffected, NMDA receptor (NMDAr)-mediated long-term potentiation (LTP) triggered by theta-burst (TBS) but not by high-frequency (HFS) stimulation was impaired in 3-hit mice. Isolated NMDAr activation was not affected or even increased in female 3-hit mice, revealing a sexual dimorphism. Considering that the regulation of LTP is more prone to inhibitory tone if triggered by TBS than by HFS, the weaker potentiation in 3-hit mice suggests a deficiency of intrinsic GABA regulatory mechanisms. Indeed, NMDAr activation was increased by GABAA receptor blockade in wild-type but not in 3-hit mice. This electrophysiological study highlights dysregulations of functional properties and plasticity in hippocampal networks of 3-hit mice, one of the mechanisms suspected to contribute to the pathophysiology of schizophrenia. It also shows differences between males and females, supporting the sexual dimorphism observed in the disorder. Combined with the previously reported study, the present data reinforce the face validity of the 3-hit model that will help to consider new therapeutic strategies for psychosis.


Assuntos
Região CA1 Hipocampal/fisiopatologia , Potenciação de Longa Duração , Esquizofrenia/fisiopatologia , Transmissão Sináptica , Ritmo Teta , Animais , Região CA1 Hipocampal/patologia , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Mutantes , Esquizofrenia/genética , Esquizofrenia/patologia
2.
Nat Commun ; 12(1): 1398, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658519

RESUMO

We previously identified a causal link between a rare patient mutation in DISC1 (disrupted-in-schizophrenia 1) and synaptic deficits in cortical neurons differentiated from isogenic patient-derived induced pluripotent stem cells (iPSCs). Here we find that transcripts related to phosphodiesterase 4 (PDE4) signaling are significantly elevated in human cortical neurons differentiated from iPSCs with the DISC1 mutation and that inhibition of PDE4 or activation of the cAMP signaling pathway functionally rescues synaptic deficits. We further generated a knock-in mouse line harboring the same patient mutation in the Disc1 gene. Heterozygous Disc1 mutant mice exhibit elevated levels of PDE4s and synaptic abnormalities in the brain, and social and cognitive behavioral deficits. Pharmacological inhibition of the PDE4 signaling pathway rescues these synaptic, social and cognitive behavioral abnormalities. Our study shows that patient-derived isogenic iPSC and humanized mouse disease models are integral and complementary for translational studies with a better understanding of underlying molecular mechanisms.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Proteínas do Tecido Nervoso/genética , Inibidores da Fosfodiesterase 4/farmacologia , Esquizofrenia/genética , Animais , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/fisiologia , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Masculino , Camundongos Mutantes , Mutação , Neurônios/efeitos dos fármacos , Rolipram/farmacologia , Esquizofrenia/patologia , Sinapses/efeitos dos fármacos , Sinapses/fisiologia
3.
Molecules ; 26(3)2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33535560

RESUMO

Brassicaceae are an outstanding source of bioactive compounds such as ascorbic acid, polyphenols, essential minerals, isothiocyanates and their precursors, glucosinolates (GSL). Recently, GSL gained great attention because of the health promoting properties of their hydrolysis products: isothiocyanates. Among them, sulforaphane (SFN) became the most attractive one owing to its remarkable health-promoting properties. SFN may prevent different types of cancer and has the ability to improve hypertensive states, to prevent type 2 diabetes-induced cardiomyopathy, and to protect against gastric ulcer. SFN may also help in schizophrenia treatment, and recently it was proposed that SFN has potential to help those who struggle with obesity. The mechanism underlying the health-promoting effect of SFN relates to its indirect action at cellular level by inducing antioxidant and Phase II detoxifying enzymes through the activation of transcription nuclear factor (erythroid-derived 2)-like (Nrf2). The effect of SFN on immune response is generating scientific interest, because of its bioavailability, which is much higher than other phytochemicals, and its capacity to induce Nrf2 target genes. Clinical trials suggest that sulforaphane produces favorable results in cases where pharmaceutical products fail. This article provides a revision about the relationship between sulforaphane and immune response in different diseases. Special attention is given to clinical trials related with immune system disorders.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Sistema Imunitário/efeitos dos fármacos , Isotiocianatos/uso terapêutico , Neoplasias/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Esquizofrenia/tratamento farmacológico , Sulfóxidos/uso terapêutico , Animais , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/patologia , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/patologia , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Esquizofrenia/imunologia , Esquizofrenia/patologia
4.
Nat Commun ; 12(1): 1142, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602941

RESUMO

Negative symptoms in schizophrenia strongly contribute to poor functional outcomes, however its pathogenesis is still unclear. Here, we found that histamine H1 receptor (H1R) expression in basal forebrain (BF) cholinergic neurons was decreased in patients with schizophrenia having negative symptoms. Deletion of H1R gene in cholinergic neurons in mice resulted in functional deficiency of cholinergic projections from the BF to the prefrontal cortex and in the formation of sensorimotor gating deficit, social impairment and anhedonia-like behavior. These behavioral deficits can be rescued by re-expressing H1R or by chemogenetic activation of cholinergic neurons in the BF. Direct chemogenetic inhibition of BF cholinergic neurons produced such behavioral deficits and also increased the susceptibility to hyperlocomotion. Our results suggest that the H1R deficiency in BF cholinergic neurons is critical for sensorimotor gating deficit, social impairments and anhedonia-like behavior. This finding may help to understand the genetic and biochemical bases of negative symptoms in schizophrenia.


Assuntos
Neurônios Colinérgicos/metabolismo , Receptores Histamínicos H1/metabolismo , Filtro Sensorial , Comportamento Social , Anedonia/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Colina O-Acetiltransferase/metabolismo , Disfunção Cognitiva/complicações , Maleato de Dizocilpina/farmacologia , Feminino , Integrases/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/patologia , Esquizofrenia/patologia
5.
PLoS Genet ; 17(1): e1009224, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33417599

RESUMO

Discovering drugs that efficiently treat brain diseases has been challenging. Genetic variants that modulate the expression of potential drug targets can be utilized to assess the efficacy of therapeutic interventions. We therefore employed Mendelian Randomization (MR) on gene expression measured in brain tissue to identify drug targets involved in neurological and psychiatric diseases. We conducted a two-sample MR using cis-acting brain-derived expression quantitative trait loci (eQTLs) from the Accelerating Medicines Partnership for Alzheimer's Disease consortium (AMP-AD) and the CommonMind Consortium (CMC) meta-analysis study (n = 1,286) as genetic instruments to predict the effects of 7,137 genes on 12 neurological and psychiatric disorders. We conducted Bayesian colocalization analysis on the top MR findings (using P<6x10-7 as evidence threshold, Bonferroni-corrected for 80,557 MR tests) to confirm sharing of the same causal variants between gene expression and trait in each genomic region. We then intersected the colocalized genes with known monogenic disease genes recorded in Online Mendelian Inheritance in Man (OMIM) and with genes annotated as drug targets in the Open Targets platform to identify promising drug targets. 80 eQTLs showed MR evidence of a causal effect, from which we prioritised 47 genes based on colocalization with the trait. We causally linked the expression of 23 genes with schizophrenia and a single gene each with anorexia, bipolar disorder and major depressive disorder within the psychiatric diseases and 9 genes with Alzheimer's disease, 6 genes with Parkinson's disease, 4 genes with multiple sclerosis and two genes with amyotrophic lateral sclerosis within the neurological diseases we tested. From these we identified five genes (ACE, GPNMB, KCNQ5, RERE and SUOX) as attractive drug targets that may warrant follow-up in functional studies and clinical trials, demonstrating the value of this study design for discovering drug targets in neuropsychiatric diseases.


Assuntos
Doença de Alzheimer/genética , Descoberta de Drogas , Predisposição Genética para Doença , Transcriptoma/genética , Doença de Alzheimer/tratamento farmacológico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Transtorno Bipolar/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Terapia de Alvo Molecular , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/patologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Esquizofrenia/patologia
6.
Neurosci Lett ; 745: 135629, 2021 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-33440236

RESUMO

There is converging evidence of dendritic spine dysfunction in schizophrenia. In the present study we hypothesized that the expression of key proteins involved in dendritic spine development and stability may be affected in schizophrenia. Postmortem frontal cortex (BA6) from patients with schizophrenia, major depressive disorder, bipolar disorder and healthy controls was processed for glutamate post-synaptic fraction extraction and post-synaptic density purification. Protein expression of the post-synaptic fraction and the post-synaptic density was assessed using immunoprecipitation and Western blotting respectively. The expression of the N-methyl-d-aspartate glutamate receptor (NMDAR) subunit NR2A, post-synaptic density 95 (PSD-95), Ca2+/calmodulin-dependent protein kinase II subunits α and ß (CaMKIIα and ß) were significantly reduced in schizophrenia. A significant decrease in the expression of NR2A was also observed in patients with major depressive disorder relative to controls, but not in patients with bipolar disorder. These results add to existing evidence for disturbed post-synaptic glutamate function and synaptic plasticity in schizophrenia. There may also be subtle disturbances in the post-synaptic glutamatergic function in major depressive disorder.


Assuntos
Proteínas de Membrana/biossíntese , Proteínas do Tecido Nervoso/biossíntese , Plasticidade Neuronal/fisiologia , Córtex Pré-Frontal/metabolismo , Esquizofrenia/metabolismo , Adulto , Proteína 4 Homóloga a Disks-Large/biossíntese , Proteína 4 Homóloga a Disks-Large/genética , Feminino , Expressão Gênica , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Córtex Pré-Frontal/patologia , Proteínas/genética , Proteínas/metabolismo , Receptores de N-Metil-D-Aspartato/biossíntese , Receptores de N-Metil-D-Aspartato/genética , Esquizofrenia/genética , Esquizofrenia/patologia
7.
Nat Neurosci ; 24(2): 214-224, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33353966

RESUMO

The complement component 4 (C4) gene is linked to schizophrenia and synaptic refinement. In humans, greater expression of C4A in the brain is associated with an increased risk of schizophrenia. To investigate this genetic finding and address how C4A shapes brain circuits in vivo, here, we generated a mouse model with primate-lineage-specific isoforms of C4, human C4A and/or C4B. Human C4A bound synapses more efficiently than C4B. C4A (but not C4B) rescued the visual system synaptic refinement deficits of C4 knockout mice. Intriguingly, mice without C4 had normal numbers of cortical synapses, which suggests that complement is not required for normal developmental synaptic pruning. However, overexpressing C4A in mice reduced cortical synapse density, increased microglial engulfment of synapses and altered mouse behavior. These results suggest that increased C4A-mediated synaptic elimination results in abnormal brain circuits and behavior. Understanding pathological overpruning mechanisms has important therapeutic implications in disease conditions such as schizophrenia.


Assuntos
Comportamento Animal , Complemento C4/genética , Esquizofrenia/genética , Psicologia do Esquizofrênico , Sinapses/patologia , Animais , Complemento C4/biossíntese , Espinhas Dendríticas/patologia , Depressão/psicologia , Feminino , Dosagem de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microglia/patologia , Rede Nervosa/patologia , Desempenho Psicomotor , Esquizofrenia/patologia , Sinaptossomos/patologia
8.
Psychiatr Danub ; 32(3-4): 359-366, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33370733

RESUMO

BACKGROUND: Schizophrenia is a severe illness whose clinical course is characterized by various numbers of psychotic episodes (PE). The neurotoxic hypothesis (NH) of schizophrenia assumes that psychosis is biologically toxic. The aim of the study was to investigate whether schizophrenia patients (SP) with multiple PE have greater grey matter volume (GMV) reduction compared to SP with fewer PE. SUBJECTS AND METHODS: We enrolled 106 adult SP and 63 healthy controls. Demographic and clinical data were collected and statistically analysed for all included subjects. Magnetic resonance imaging (MRI) of the brain was acquired on a 1.5 T scanner. SP were grouped according to the number of PE into a group with up to 3 PE (SCHG-1) and with 4 or more PE (SCHG-2). SCHG-1 was further subdivided into two groups regarding to disease duration (DD). Voxel-based morphometry (VBM) analyses were performed between SP groups as well as between SP groups and the healthy controls group (HCG). RESULTS: No relevant GMV differences were detected between SP groups. Comparison between HCG and SCHG-1 showed only 3 regions with reduced GMV, while multiple regions with reduced GMV were detected when comparing HCG and SCHG-2. CONCLUSIONS: GMV reduction in schizophrenia varies depending on the number of PE when compared to HCG, regardless of disease duration (DD), but PE is not the only contributing factor that leads to neurotoxicity.


Assuntos
Encéfalo/patologia , Substância Cinzenta/patologia , Transtornos Psicóticos/patologia , Esquizofrenia/patologia , Adulto , Encéfalo/diagnóstico por imagem , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Transtornos Psicóticos/diagnóstico por imagem , Esquizofrenia/diagnóstico por imagem
9.
Croat Med J ; 61(4): 354-365, 2020 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-32881434

RESUMO

AIM: To analyze axon morphology on rapid Golgi impregnated pyramidal neurons in the dorsolateral prefrontal cortex in schizophrenia. METHODS: Postmortem brain tissue from five subjects diagnosed with schizophrenia and five control subjects without neuropathological findings was processed with the rapid Golgi method. Layer III and layer V pyramidal neurons from Brodmann area 9 were chosen in each brain for reconstruction with Neurolucida software. The axons and cell bodies of 136 neurons from subjects with schizophrenia and of 165 neurons from control subjects were traced. The data obtained by quantitative analysis were compared between the schizophrenia and control group with the t test. RESULTS: Axon impregnation length was consistently greater in the schizophrenia group. The axon main trunk length was significantly greater in the schizophrenia than in the control group (93.7 ± 36.6 µm vs 49.8 ± 9.9 µm, P = 0.032). Furthermore, in the schizophrenia group more axons had visibly stained collaterals (14.7% vs 5.5%). CONCLUSION: Axon rapid Golgi impregnation stops at the beginning of the myelin sheath. The increased axonal staining in the schizophrenia group could, therefore, be explained by reduced axon myelination. Such a decrease in axon myelination is in line with both the disconnection hypothesis and the two-hit model of schizophrenia as a neurodevelopmental disease. Our results support that the cortical circuitry disorganization in schizophrenia might be caused by functional alterations of two major classes of principal neurons due to altered oligodendrocyte development.


Assuntos
Axônios/patologia , Córtex Pré-Frontal/patologia , Células Piramidais/patologia , Esquizofrenia/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Complexo de Golgi/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Coloração e Rotulagem/métodos
10.
Artigo em Inglês | MEDLINE | ID: mdl-32867189

RESUMO

Little is known regarding the neuroanatomical correlates of patients with deficit schizophrenia or persistent negative symptoms. In this meta-analysis, we aimed to determine whether patients with deficit schizophrenia have characteristic brain abnormalities. We searched PubMed, CINAHL and Ovid to identify studies that examined the various regions of interest amongst patients with deficit schizophrenia, patients with non-deficit schizophrenia and healthy controls. A total of 24 studies met our inclusion criteria. A random-effects model was used to calculate a combination of outcome measures, and heterogeneity was assessed by the I2 statistic and Cochran's Q statistic. Our findings suggested that there was statistically significant reduction in grey matter volume (-0.433, 95% confidence interval (CI): -0.853 to -0.014, p = 0.043) and white matter volume (-0.319, 95% CI: -0.619 to -0.018, p = 0.038) in patients with deficit schizophrenia compared to healthy controls. There is also statistically significant reduction in total brain volume (-0.212, 95% CI: -0.384 to -0.041, p = 0.015) and white matter volume (-0.283, 95% CI: -0.546 to -0.021, p = 0.034) in patients with non-deficit schizophrenia compared to healthy controls. Between patients with deficit and non-deficit schizophrenia, there were no statistically significant differences in volumetric findings across the various regions of interest.


Assuntos
Imagem por Ressonância Magnética/métodos , Neuroanatomia , Esquizofrenia/patologia , Substância Branca/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Humanos , Masculino , Neuroimagem
11.
PLoS One ; 15(7): e0235409, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726314

RESUMO

OBJECTIVES: To identify inequalities in cancer survival rates for patients with a history of severe psychiatric illness (SPI) compared to those with no history of mental illness and explore differences in the provision of recommended cancer treatment as a potential explanation. DESIGN: Population-based retrospective cohort study using linked cancer registry and administrative data at ICES. SETTING: The universal healthcare system in Ontario, Canada. PARTICIPANTS: Colorectal cancer (CRC) patients diagnosed between April 1st, 2007 and December 31st, 2012. SPI history (schizophrenia, schizoaffective disorders, other psychotic disorders, bipolar disorders or major depressive disorders) was determined using hospitalization, emergency department, and psychiatrist visit data and categorized as 'no history of mental illness, 'outpatient SPI history', and 'inpatient SPI history'. MAIN OUTCOME MEASURES: Cancer-specific survival, non-receipt of surgical resection, and non-receipt of adjuvant chemotherapy or radiation. RESULTS: 24,507 CRC patients were included; 482 (2.0%) had an outpatient SPI history and 258 (1.0%) had an inpatient SPI history. Individuals with an SPI history had significantly lower survival rates and were significantly less likely to receive guideline recommended treatment than CRC patients with no history of mental illness. The adjusted HR for cancer-specific death was 1.69 times higher for individuals with an inpatient SPI (95% CI 1.36-2.09) and 1.24 times higher for individuals with an outpatient SPI history (95% CI 1.04-1.48). Stage II and III CRC patients with an inpatient SPI history were 2.15 times less likely (95% CI 1.07-4.33) to receive potentially curative surgical resection and 2.07 times less likely (95% CI 1.72-2.50) to receive adjuvant radiation or chemotherapy. These findings were consistent across multiple sensitivity analyses. CONCLUSIONS: Individuals with an SPI history experience inequalities in colorectal cancer care and survival within a universal healthcare system. Increasing advocacy and the availability of resources to support individuals with an SPI within the cancer system are warranted to reduce the potential for unnecessary harm.


Assuntos
Transtorno Bipolar/terapia , Neoplasias Colorretais/terapia , Transtorno Depressivo Maior/terapia , Esquizofrenia/terapia , Adulto , Transtorno Bipolar/complicações , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/patologia , Sobreviventes de Câncer/psicologia , Quimioterapia Adjuvante , Estudos de Coortes , Neoplasias Colorretais/complicações , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/patologia , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/patologia , Serviço Hospitalar de Emergência , Feminino , Hospitalização , Humanos , Pacientes Internados/psicologia , Masculino , Pessoa de Meia-Idade , Ontário/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Esquizofrenia/complicações , Esquizofrenia/epidemiologia , Esquizofrenia/patologia
12.
PLoS One ; 15(7): e0230400, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32639965

RESUMO

Alterations in the cortico-cerebellar-thalamic-cortical circuit might underlie the diversity of symptoms in schizophrenia. However, molecular changes in cerebellar neuronal circuits, part of this network, have not yet been fully determined. Using LC-MS/MS, we screened altered candidates in pooled grey matter of cerebellum from schizophrenia subjects who committed suicide (n = 4) and healthy individuals (n = 4). Further validation by immunoblotting of three selected candidates was performed in two cohorts comprising schizophrenia (n = 20), non-schizophrenia suicide (n = 6) and healthy controls (n = 21). We found 99 significantly altered proteins, 31 of them previously reported in other brain areas by proteomic studies. Transport function was the most enriched category, while cell communication was the most prevalent function. For validation, we selected the vacuolar proton pump subunit 1 (VPP1), from transport, and two EF-hand calcium-binding proteins, calmodulin and parvalbumin, from cell communication. All candidates showed significant changes in schizophrenia (n = 7) compared to controls (n = 7). VPP1 was altered in the non-schizophrenia suicide group and increased levels of parvalbumin were linked to antipsychotics. Further validation in an independent cohort of non-suicidal chronic schizophrenia subjects (n = 13) and non-psychiatric controls (n = 14) showed that parvalbumin was increased, while calmodulin was decreased in schizophrenia. Our findings provide evidence of calcium-binding protein dysregulation in the cerebellum in schizophrenia, suggesting an impact on normal calcium-dependent synaptic functioning of cerebellar circuits. Our study also links VPP1 to suicide behaviours, suggesting a possible impairment in vesicle neurotransmitter refilling and release in these phenotypes.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Cerebelo/metabolismo , Esquizofrenia/patologia , Adulto , Calmodulina/metabolismo , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Regulação para Baixo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Parvalbuminas/metabolismo , Proteoma/análise , Esquizofrenia/metabolismo , Tentativa de Suicídio , Espectrometria de Massas em Tandem , Regulação para Cima
13.
J Fr Ophtalmol ; 43(7): 586-597, 2020 Sep.
Artigo em Francês | MEDLINE | ID: mdl-32631695

RESUMO

Major depressive disorder, bipolar disorder and schizophrenia are currently among the most common psychiatric disorders, known to constitute a serious public health issue in terms of morbidity, mortality and functional handicap. Their pathophysiology is still unclear, but there is now increasing evidence supporting the existence of abnormalities of neurotransmission. As the retina is an extension of the central nervous system, it may be an interesting site of study which might provide a better understanding of the pathophysiology of psychiatric disorders. Several studies have demonstrated retinal abnormalities, with abnormal cone and rod responses on electroretinography (ERG), suggesting a process of functional neuronal loss, structurally supported by a decrease in the retinal nerve fiber layer thickness (RNFL) on optical coherence tomography (OCT), which suggests involvement of the molecular signal pathways of neurotransmission. These tests could be useful tools for diagnosing and monitoring psychiatric disorders. This article is an overview of the literature on retinal abnormalities observed in patients with major depressive disorder, bipolar disorder or schizophrenia, and discusses how they could be pathophysiologic markers.


Assuntos
Transtorno Bipolar/fisiopatologia , Transtorno Depressivo Maior/fisiopatologia , Retina/diagnóstico por imagem , Retina/fisiologia , Esquizofrenia/fisiopatologia , Acuidade Visual/fisiologia , Transtorno Bipolar/complicações , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/patologia , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/patologia , Eletrorretinografia , Humanos , Fibras Nervosas/patologia , Fibras Nervosas/fisiologia , Retina/patologia , Células Fotorreceptoras Retinianas Cones/patologia , Células Fotorreceptoras Retinianas Cones/fisiologia , Células Ganglionares da Retina/patologia , Células Ganglionares da Retina/fisiologia , Esquizofrenia/complicações , Esquizofrenia/diagnóstico , Esquizofrenia/patologia , Tomografia de Coerência Óptica
14.
PLoS Genet ; 16(7): e1008785, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32628676

RESUMO

To efficiently transform genetic associations into drug targets requires evidence that a particular gene, and its encoded protein, contribute causally to a disease. To achieve this, we employ a three-step proteome-by-phenome Mendelian Randomization (MR) approach. In step one, 154 protein quantitative trait loci (pQTLs) were identified and independently replicated. From these pQTLs, 64 replicated locally-acting variants were used as instrumental variables for proteome-by-phenome MR across 846 traits (step two). When its assumptions are met, proteome-by-phenome MR, is equivalent to simultaneously running many randomized controlled trials. Step 2 yielded 38 proteins that significantly predicted variation in traits and diseases in 509 instances. Step 3 revealed that amongst the 271 instances from GeneAtlas (UK Biobank), 77 showed little evidence of pleiotropy (HEIDI), and 92 evidence of colocalization (eCAVIAR). Results were wide ranging: including, for example, new evidence for a causal role of tyrosine-protein phosphatase non-receptor type substrate 1 (SHPS1; SIRPA) in schizophrenia, and a new finding that intestinal fatty acid binding protein (FABP2) abundance contributes to the pathogenesis of cardiovascular disease. We also demonstrated confirmatory evidence for the causal role of four further proteins (FGF5, IL6R, LPL, LTA) in cardiovascular disease risk.


Assuntos
Doenças Cardiovasculares/genética , Análise da Randomização Mendeliana , Proteoma/genética , Esquizofrenia/genética , Antígenos de Diferenciação/genética , Doenças Cardiovasculares/patologia , Proteínas de Ligação a Ácido Graxo/genética , Feminino , Fator 5 de Crescimento de Fibroblastos/genética , Estudos de Associação Genética/métodos , Humanos , Lipase Lipoproteica/genética , Linfotoxina-alfa/genética , Masculino , Locos de Características Quantitativas , Receptores Imunológicos/genética , Receptores de Interleucina-6/genética , Esquizofrenia/patologia
15.
Nat Commun ; 11(1): 3089, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32555168

RESUMO

Electroencephalogram microstates are recurrent scalp potential configurations that remain stable for around 90 ms. The dynamics of two of the four canonical classes of microstates, commonly labeled as C and D, have been suggested as a potential endophenotype for schizophrenia. For endophenotypes, unaffected relatives of patients must show abnormalities compared to controls. Here, we examined microstate dynamics in resting-state recordings of unaffected siblings of patients with schizophrenia, patients with schizophrenia, healthy controls, and patients with first episodes of psychosis (FEP). Patients with schizophrenia and their siblings showed increased presence of microstate class C and decreased presence of microstate class D compared to controls. No difference was found between FEP and chronic patients. Our findings suggest that the dynamics of microstate classes C and D are a candidate endophenotype for schizophrenia.


Assuntos
Eletroencefalografia/métodos , Esquizofrenia/patologia , Endofenótipos , Feminino , Humanos , Masculino , Transtornos Psicóticos/patologia
16.
PLoS One ; 15(5): e0232826, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32379845

RESUMO

This study aimed to investigate abnormalities in the gray matter and white matter (GM and WM, respectively) that are shared between schizophrenia (SZ) and bipolar disorder (BD). We used 3T-magnetic resonance imaging to examine patients with SZ, BD, or healthy control (HC) subjects (aged 20-50 years, N = 65 in each group). We generated modulated GM maps through voxel-based morphometry (VBM) for T1-weighted images and skeletonized fractional anisotropy, mean diffusion, and radial diffusivity maps through tract-based special statistics (TBSS) methods for diffusion tensor imaging (DTI) data. These data were analyzed using a generalized linear model with pairwise comparisons between groups with a family-wise error corrected P < 0.017. The VBM analysis revealed widespread decreases in GM volume in SZ compared to HC, but patients with BD showed GM volume deficits limited to the right thalamus and left insular lobe. The TBSS analysis showed alterations of DTI parameters in widespread WM tracts both in SZ and BD patients compared to HC. The two disorders had WM alterations in the corpus callosum, superior longitudinal fasciculus, internal capsule, external capsule, posterior thalamic radiation, and fornix. However, we observed no differences in GM volume or WM integrity between SZ and BD. The study results suggest that GM volume deficits in the thalamus and insular lobe along with widespread disruptions of WM integrity might be the common neural mechanisms underlying the pathologies of SZ and BD.


Assuntos
Transtorno Bipolar/patologia , Substância Cinzenta/patologia , Esquizofrenia/patologia , Substância Branca/patologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
17.
Nat Commun ; 11(1): 2329, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393757

RESUMO

Impaired cognitive functioning is a core feature of schizophrenia, and is hypothesized to be due to myelination as well as interneuron defects during adolescent prefrontal cortex (PFC) development. Here we report that in the apomorphine-susceptible (APO-SUS) rat model, which has schizophrenia-like features, a myelination defect occurred specifically in parvalbumin interneurons. The adult rats displayed medial PFC (mPFC)-dependent cognitive inflexibility, and a reduced number of mature oligodendrocytes and myelinated parvalbumin inhibitory axons in the mPFC. In the developing mPFC, we observed decreased myelin-related gene expression that persisted into adulthood. Environmental enrichment applied during adolescence restored parvalbumin interneuron hypomyelination as well as cognitive inflexibility. Collectively, these findings highlight that impairment of parvalbumin interneuron myelination is related to schizophrenia-relevant cognitive deficits.


Assuntos
Cognição/fisiologia , Interneurônios/patologia , Bainha de Mielina/patologia , Esquizofrenia/patologia , Esquizofrenia/fisiopatologia , Animais , Axônios/metabolismo , Axônios/ultraestrutura , Linhagem da Célula , Modelos Animais de Doenças , Neurônios GABAérgicos/metabolismo , Regulação da Expressão Gênica , Interneurônios/ultraestrutura , Aprendizagem , Bainha de Mielina/ultraestrutura , Oligodendroglia/patologia , Parvalbuminas/metabolismo , Córtex Pré-Frontal/fisiopatologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar
18.
Psychiatry Res Neuroimaging ; 300: 111084, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32388386

RESUMO

In this study, we explored the relationship between baseline hippocampal subfield volumes and change in body mass over 12 months of treatment in 90 first-episode schizophrenia spectrum disorder patients (66 males, 24 females; mean age= 24.7 ± 6.8 years). Body mass index was assessed in patients at baseline, and at months 3, 6, 9 and 12. Hippocampal subfields of interest were assessed at baseline using a segmentation algorithm included in the FreeSurfer 6.0 software program. Linear regression revealed a significant interactive effect between sex and anterior hippocampus size as predictors of change in body mass over 12 months, adjusting for age, substance use, and treatment duration. In an exploratory post-hoc sub-analysis, partial correlations showed a significant association between weight gain and smaller CA1, CA3 and subiculum volumes in females, but not males, adjusting for age and substance use, with similar trends evident for the CA4 and presubiculum subfields. In conclusion, our findings suggest that smaller anterior hippocampal subfields at baseline are associated with the development of weight gain over the course of treatment in first-episode schizophrenia spectrum disorders in a sex-specific fashion. This may be related to the greater increase in body mass evident for female patients in our study.


Assuntos
Antipsicóticos/uso terapêutico , Índice de Massa Corporal , Hipocampo/patologia , Esquizofrenia/patologia , Adulto , Feminino , Hipocampo/diagnóstico por imagem , Humanos , Modelos Lineares , Imagem por Ressonância Magnética , Masculino , Tamanho do Órgão/efeitos dos fármacos , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/tratamento farmacológico , Resultado do Tratamento , Adulto Jovem
19.
BMC Med Genet ; 21(1): 85, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32316934

RESUMO

BACKGROUND: Previous studies found that Ser9Gly (rs6280) might be involved in the occurrence of schizophrenia. However, no consist conclusion has yet been achieved. Compared to the case-control study, the family-based study took into account stratification bias. Thus, we conducted a meta-analysis of family-based studies to measure a pooled effect size of the association between Ser9Gly and the risk of schizophrenia. METHODS: The relevant family-based studies were screened using the electronic databases by the inclusion criteria. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to measure the correction between Ser9Gly polymorphism and schizophrenia susceptibility. Subgroup analysis was performed by stratification of ethnicity (i.e., East Asian, Caucasian, and other populations). Additionally, publication bias was evaluated by the funnel plot. RESULTS: After literature searching, a total of 13 family-based association studies were included, which contained 11 transmission disequilibrium test (TDT) studies with 1219 informative meiosis and 5 haplotype-based haplotype relative risk (HRR) studies. No statistical significance of the heterogeneity was detected in TDT and HRR studies. Thus, the pooled effect size was calculated under the fixed effect model. The results found that the association was significantly protective in East Asian in TDT studies (204 informative meiosis, OR = 0.744, 95% CI = 0.564-0.980, Z-value = - 2.104, p = 0.035). CONCLUSIONS: The meta-analysis based on the family study found a protective association of Ser9Gly in East Asian. In future, large sample molecular epidemiology studies are needed to validate our findings.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Receptores de Dopamina D3/genética , Esquizofrenia/genética , Alelos , Substituição de Aminoácidos/genética , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu , Feminino , Frequência do Gene , Genótipo , Haplótipos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Esquizofrenia/patologia
20.
PLoS One ; 15(4): e0231669, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32320431

RESUMO

Subtle abnormalities in sensory integration, motor coordination and sequencing of complex motor acts or neurological soft signs (NSS) are characteristic phenomena in patients with schizophrenia at any stage of the illness. Previous MRI studies in schizophrenia found NSS to be associated with cortical, thalamic and cerebellar changes. Since these studies mainly focused on first-episode or recent onset schizophrenia, the cerebral correlates of NSS in chronic schizophrenia remained rather unclear. 49 middle-aged patients with chronic schizophrenia with a mean duration of illness of 20.3 ± 14.0 years and 29 healthy subjects matched for age and sex were included. NSS were examined on the Heidelberg Scale and correlated to grey matter (GM) by using whole brain high resolution magnetic resonance imaging (3 Tesla) with SPM12/CAT12 analyses. As expected, NSS in patients were significantly (p≤0.001) elevated in contrast to healthy controls, a finding, which not only applied to NSS total score, but also to the respective subscales "motor coordination", "sensory integration", "complex motor tasks", "right/left and spatial orientation" and "hard signs". Within the patient group NSS total scores were significantly correlated to reduced GM in right lingual gyrus, left parahippocampal gyrus, left superior temporal gyrus, left thalamus (medial dorsal nucleus) and left posterior lobe of the cerebellum (declive). Respective negative associations could also be revealed for the subscales "motor coordination", "complex motor tasks" and "right/left and spatial orientation". These findings remained significant after FWE-correction for multiple comparisons and were confirmed when years of education, chlorpromazine-equivalents or variables indicating the severity of psychopathology were introduced as additional covariates. According to our results lingual, parahippocampal, superior temporal, inferior and middle frontal gyri, thalamus and cerebellum have to be considered as important sites of NSS in chronic schizophrenia. That these findings only applied for patients but not healthy controls may indicate a different pathogenesis of NSS.


Assuntos
Encéfalo/diagnóstico por imagem , Esquizofrenia/diagnóstico por imagem , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Destreza Motora , Percepção , Esquizofrenia/patologia
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