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1.
Cell Rep ; 39(5): 110790, 2022 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-35508131

RESUMO

Heterozygous loss-of-function (LoF) mutations in SETD1A, which encodes a subunit of histone H3 lysine 4 methyltransferase, cause a neurodevelopmental syndrome and increase the risk for schizophrenia. Using CRISPR-Cas9, we generate excitatory/inhibitory neuronal networks from human induced pluripotent stem cells with a SETD1A heterozygous LoF mutation (SETD1A+/-). Our data show that SETD1A haploinsufficiency results in morphologically increased dendritic complexity and functionally increased bursting activity. This network phenotype is primarily driven by SETD1A haploinsufficiency in glutamatergic neurons. In accordance with the functional changes, transcriptomic profiling reveals perturbations in gene sets associated with glutamatergic synaptic function. At the molecular level, we identify specific changes in the cyclic AMP (cAMP)/Protein Kinase A pathway pointing toward a hyperactive cAMP pathway in SETD1A+/- neurons. Finally, by pharmacologically targeting the cAMP pathway, we are able to rescue the network deficits in SETD1A+/- cultures. Our results demonstrate a link between SETD1A and the cAMP-dependent pathway in human neurons.


Assuntos
Células-Tronco Pluripotentes Induzidas , Esquizofrenia , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Neurônios/metabolismo , Esquizofrenia/genética , Esquizofrenia/metabolismo
2.
Stem Cell Res ; 61: 102766, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35367693

RESUMO

Schizophrenia is a chronic, serious and disabling mental disorder. Most patients can effectively control their condition through drug treatment, but there are still some patients who are difficult to gain benefits from drug treatment. Among them, the failure to respond to clozapine full-scale treatment is ultra-treatment-resistant schizophrenia. We generated induced pluripotent stem cells (iPSCs) from an ultra-treatment-resistant schizophrenia patient by electroporation of peripheral blood mononuclear cells (PBMCs) with episomal plasmids encoding OCT 4, SOX 2, NANOG, LIN 28, KLF 4 and MYC. The iPSCs demonstrated normal karyotype, expressed pluripotency markers and differentiated into the three germ layers in vivo.


Assuntos
Células-Tronco Pluripotentes Induzidas , Esquizofrenia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Leucócitos Mononucleares/metabolismo , Esquizofrenia/genética , Esquizofrenia/metabolismo , Fatores de Transcrição/metabolismo
3.
Transl Psychiatry ; 12(1): 168, 2022 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-35459266

RESUMO

Blockade of N-methyl-D-aspartate receptors (NMDAR) is known to augment cortical serotonin 2A receptors (5-HT2ARs), which is implicated in psychosis. However, the pathways from NMDAR hypofunction to 5-HT2AR up-regulation are unclear. Here we addressed in mice whether genetic deletion of the indispensable NMDAR-subunit Grin1 principally in corticolimbic parvalbumin-positive fast-spiking interneurons, could up-regulate 5-HT2ARs leading to cortical hyper-excitability. First, in vivo local-field potential recording revealed that auditory cortex in Grin1 mutant mice became hyper-excitable upon exposure to acoustic click-train stimuli that release 5-HT in the cortex. This excitability increase was reproduced ex vivo where it consisted of an increased frequency of action potential (AP) firing in layer 2/3 pyramidal neurons of mutant auditory cortex. Application of the 5-HT2AR agonist TCB-2 produced similar results. The effect of click-trains was reversed by the 5-HT2AR antagonist M100907 both in vivo and ex vivo. Increase in AP frequency of pyramidal neurons was also reversed by application of Gαq protein inhibitor BIM-46187 and G protein-gated inwardly-rectifying K+ (GIRK) channel activator ML297. In fast-spiking interneurons, 5-HT2AR activation normally promotes GABA release, contributing to decreased excitability of postsynaptic pyramidal neurons, which was missing in the mutants. Moreover, unlike the controls, the GABAA receptor antagonist (+)-bicuculline had little effect on AP frequency of mutant pyramidal neurons, indicating a disinhibition state. These results suggest that the auditory-induced hyper-excitable state is conferred via GABA release deficits from Grin1-lacking interneurons leading to 5-HT2AR dysregulation and GIRK channel suppression in cortical pyramidal neurons, which could be involved in auditory psychosis.


Assuntos
Receptores de N-Metil-D-Aspartato , Esquizofrenia , Animais , Modelos Animais de Doenças , Camundongos , Células Piramidais/metabolismo , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/genética , Esquizofrenia/metabolismo , Ácido gama-Aminobutírico/metabolismo
4.
Sci Adv ; 8(9): eabm1077, 2022 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-35245111

RESUMO

Schizophrenia (SCZ) is a chronic, serious mental disorder. Although more than 200 SCZ-associated genes have been identified, the underlying molecular and cellular mechanisms remain largely unknown. Here, we generated a Setd1a (SET domain containing 1A) haploinsufficiency mouse model to understand how this SCZ-associated epigenetic factor affects gene expression in brain regions highly relevant to SCZ. Single-cell RNA sequencing revealed that Setd1a heterozygosity causes highly variable transcriptional adaptations across different cell types in prefrontal cortex (PFC) and striatum. The Foxp2+ neurons exhibit the most prominent gene expression changes among the different neuron subtypes in PFC, which correlate with changes in histone H3 lysine 4 trimethylation. Many of the genes dysregulated in Setd1a+/- mice are involved in neuron morphogenesis and synaptic function. Consistently, Setd1a+/- mice exhibit certain behavioral features of patients with SCZ. Collectively, our study establishes Setd1a+/- mice as a model for understanding SCZ and uncovers a complex brain region- and cell type-specific dysregulation that potentially underlies SCZ pathogenesis.


Assuntos
Esquizofrenia , Animais , Encéfalo/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Camundongos , Neurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Esquizofrenia/genética , Esquizofrenia/metabolismo
5.
Acta Psychiatr Scand ; 145(5): 494-506, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35243618

RESUMO

OBJECTIVE: Difficulties in social cognition are common in individuals with schizophrenia (SZ) and are not ameliorated by antipsychotic treatment. Intranasal oxytocin (OT) administration has been explored as a potential intervention to improve social cognition; however, results are inconsistent, suggesting potential individual difference variables that may influence treatment response. Less is known about the relationship between endogenous OT and social cognition in SZ, knowledge of which may improve the development of OT-focused therapies. We examined plasma OT in relationship to facial emotion recognition and visual attention to salient facial features in SZ and controls. METHODS: Forty-two individuals with SZ and 23 healthy controls viewed photographs of facial expressions of varying emotional intensity and identified the emotional expression displayed. Participants' gaze behavior during the task was recorded via eye tracking. Plasma oxytocin concentrations were determined by radioimmunoassay. RESULTS: SZ were less accurate than controls at identifying high-intensity fearful facial expressions and low-intensity sad expressions. Lower overall and high-intensity facial emotion recognition accuracy was associated with lower plasma OT levels in SZ but not controls. OT was not associated with visual attention to salient facial features; however, SZ had reduced visual attention to the nose region compared to controls. CONCLUSION: Individual differences in endogenous OT predict facial emotion recognition ability in SZ but are not associated with visual attention to salient facial features. Increased understanding of the association between endogenous OT and social cognitive abilities in SZ may help improve the design and interpretation of OT-focused clinical trials in SZ.


Assuntos
Reconhecimento Facial , Ocitocina , Esquizofrenia , Emoções , Expressão Facial , Humanos , Ocitocina/metabolismo , Esquizofrenia/metabolismo , Psicologia do Esquizofrênico , Percepção Social
6.
Cell Mol Life Sci ; 79(3): 180, 2022 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-35254515

RESUMO

Abnormal mossy fiber connections in the hippocampus have been implicated in schizophrenia. However, it remains unclear whether this abnormality in the patients is genetically determined and whether it contributes to the onset of schizophrenia. Here, we showed that iPSC-derived hippocampal NPCs from schizophrenia patients with the A/A allele at SNP rs16864067 exhibited abnormal NPC polarity, resulting from the downregulation of SOX11 by this high-risk allele. In the SOX11-deficient mouse brain, abnormal NPC polarity was also observed in the hippocampal dentate gyrus, and this abnormal NPC polarity led to defective hippocampal neurogenesis-specifically, irregular neuroblast distribution and disrupted granule cell morphology. As granule cell synapses, the mossy fiber pathway was disrupted, and this disruption was resistant to activity-induced mossy fiber remodeling in SOX11 mutant mice. Moreover, these mutant mice exhibited diminished PPI and schizophrenia-like behaviors. Activation of hippocampal neurogenesis in the embryonic brain, but not in the adult brain, partially alleviated disrupted mossy fiber connections and improved schizophrenia-related behaviors in mutant mice. We conclude that disrupted mossy fiber connections are genetically determined and strongly correlated with schizophrenia-like behaviors in SOX11-deficient mice. This disruption may reflect the pathological substrate of SOX11-associated schizophrenia.


Assuntos
Fibras Musgosas Hipocampais/metabolismo , Neurogênese , Fatores de Transcrição SOXC/fisiologia , Esquizofrenia/metabolismo , Animais , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Camundongos , Camundongos Transgênicos , Fibras Musgosas Hipocampais/fisiopatologia , Fatores de Transcrição SOXC/genética , Esquizofrenia/fisiopatologia , Sinapses
7.
Neurosci Lett ; 777: 136581, 2022 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-35337952

RESUMO

BACKGROUND: Mounting evidence suggests that the innate immune system is disrupted in schizophrenia patients with tardive dyskinesia (TD); however, the role of the toll-like receptor 4 (TLR4) signaling pathway remains unclear. METHODS: In this study, we quantified the expression of the monocytic TLR4 signaling pathway using flow cytometry, before and after lipopolysaccharide (LPS) stimulation, in chronic schizophrenia patients with (n = 61) and without TD (NTD, n = 61) and healthy controls (HCs, n = 74). Psychopathological symptoms, the severity of TD, and cognitive function were assessed using the Positive and Negative Syndrome Scale (PANSS), Abnormal Involuntary Movement Scale (AIMS), and MATRICS Consensus Cognitive Battery (MCCB), respectively. RESULTS: 1) Both TD and NTD patients showed higher TLR4 signaling pathway activity at baseline than that in HCs, but their responses to LPS were weaker than those in HCs; 2) the alteration of the TLR4 signaling pathway was less severe in TD patients than in NTD patients; 3) TLR4 levels and MCCB scores were negatively correlated at baseline but positively correlated after LPS stimulation in TD patients; 4) there was no correlation between the TLR4 signals and PANSS or AIMS scores. CONCLUSIONS: Our findings suggested the TLR4 signaling pathway disturbance might be related to cognitive deficits in schizophrenia patients with TD.


Assuntos
Esquizofrenia , Discinesia Tardia , Cognição , Humanos , Esquizofrenia/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like
8.
Neuropharmacology ; 208: 108982, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35151699

RESUMO

In schizophrenia, mGlu5 receptor hypofunction has been linked with neuropathology and cognitive deficits, making it an attractive therapeutic target. The cognitive impairment associated with schizophrenia remains an unmet clinical need, with existing antipsychotics primarily targeting positive symptoms, with weaker and more variable effects on cognitive deficits. Using the sub-chronic phencyclidine rat model, widely shown to mimic the cognitive impairment and neuropathology of schizophrenia, we have investigated two mGlu5 receptor positive allosteric modulators (PAMs), VU0409551 and VU0360172. We compared the efficacy of these compounds in restoring cognitive deficits and, since these two PAMs have reportedly distinct signalling mechanisms, changes in mGlu5 receptor signalling molecules AKT and MAPK in the PFC. Although not effective at 0.05 and 1 mg/kg, cognitive deficits were significantly alleviated by both PAMs at 10 and 20 mg/kg. The compounds appeared to have differential effects on the scPCP-induced increases in AKT and MAPK phosphorylation: VU0409551 induced a significant decrease in expression of p-AKT, whereas VU0360172 had this effect on p-MAPK levels. Thus, the beneficial effects of PAMs on scPCP-induced cognitive impairment are accompanied by at least partial reversal of scPCP-induced elevated levels of p-MAPK and p-AKT, whose dysfunction is strongly implicated in schizophrenia pathology. These promising data imply an important role for mGlu5 receptor signalling pathways in improving cognition in the scPCP model and provide support for mGlu5 receptor PAMs as a possible therapeutic intervention for schizophrenia.


Assuntos
Receptor de Glutamato Metabotrópico 5 , Esquizofrenia , Regulação Alostérica , Animais , Cognição , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Oxazóis , Fenciclidina/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas , Ratos , Receptor de Glutamato Metabotrópico 5/metabolismo , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo
9.
Eur J Med Chem ; 232: 114193, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35176563

RESUMO

Schizophrenia is a serious mental disorder without a fully understood pathomechanism, but which involves dysregulation of neurotransmitters and their receptors. The best option for the management of schizophrenia comprises so-called multi-target ligands, similar to the third generation of neuroleptics. Dopamine type 2 receptors (D2Rs) are the main target in the treatment of schizophrenia, in particular for mitigation of the positive symptoms. Due to the high expression of 5-hydroxytryptamine type 3 receptors (5-HT3Rs) in human brain areas responsible for emotional behavior, motivation, and cognitive function, 5-HT3Rs represent a potential target for modulating the cognitive and negative symptoms of schizophrenia. Here we present the design, synthesis, and both in vitro and in vivo biological evaluation of 1,4-disubstituted aromatic piperazines. Screening of in vitro properties revealed the two most promising drug candidates (21 and 24) which were found to be potent D2Rs and moderate 5-HT3R antagonists, and which were forwarded to in vivo studies in Wistar rats. Considering toxicity, administration of the maximal feasible dose of 21 (2 mg/kg) did not produce any side effects. By contrast, the higher solubility of 24 led to revelation of mild and temporary side effects at the dose of 20 mg/kg. Importantly, both 21 and 24 showed facile crossing of the blood-brain barrier, even exerting higher levels in the brain in comparison to plasma. In a behavioral study using the acute amphetamine model of psychosis, we showed that compound 24 ameliorated both positive and negative effects of amphetamine including hyperlocomotion, social impairments, and disruption of prepulse inhibition. The effect of the highest dose (10 mg/kg) was comparable to the effect of the reference dose of aripiprazole (1 mg/kg).


Assuntos
Antipsicóticos , Esquizofrenia , Animais , Antipsicóticos/efeitos adversos , Piperazinas/farmacologia , Ratos , Ratos Wistar , Receptores de Serotonina , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo
10.
Biomolecules ; 12(2)2022 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-35204828

RESUMO

Schizophrenia (SCZ) is a polygenic severe mental illness. Genome-wide association studies (GWAS) have detected genomic variants associated with this psychiatric disorder and pathway analyses have indicated immune system and dopamine signaling as core components of risk in dorsolateral-prefrontal cortex (DLPFC) and hippocampus, but the mechanistic links remain unknown. The RasGRP1 gene, encoding for a guanine nucleotide exchange factor, is implicated in dopamine signaling and immune response. RasGRP1 has been identified as a candidate risk gene for SCZ and autoimmune disease, therefore representing a possible point of convergence between mechanisms involving the nervous and the immune system. Here, we investigated RasGRP1 mRNA and protein expression in post-mortem DLPFC and hippocampus of SCZ patients and healthy controls, along with RasGRP1 protein content in the serum of an independent cohort of SCZ patients and control subjects. Differences in RasGRP1 expression between SCZ patients and controls were detected both in DLPFC and peripheral blood of samples analyzed. Our results indicate RasGRP1 may mediate risk for SCZ by involving DLPFC and peripheral blood, thus encouraging further studies to explore its possible role as a biomarker of the disease and/or a target for new medication.


Assuntos
Proteínas de Ligação a DNA , Fatores de Troca do Nucleotídeo Guanina , Esquizofrenia , Encéfalo/metabolismo , Proteínas de Ligação a DNA/metabolismo , Dopamina/metabolismo , Estudo de Associação Genômica Ampla , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Córtex Pré-Frontal/metabolismo , Esquizofrenia/genética , Esquizofrenia/metabolismo , Soro
11.
Nat Commun ; 13(1): 798, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-35145085

RESUMO

Mutations in the putative glutamatergic synapse scaffolding protein SAP97 are associated with the development of schizophrenia in humans. However, the role of SAP97 in synaptic regulation is unclear. Here we show that SAP97 is expressed in the dendrites of granule neurons in the dentate gyrus but not in the dendrites of other hippocampal neurons. Schizophrenia-related perturbations of SAP97 did not affect CA1 pyramidal neuron synapse function. Conversely, these perturbations produce dramatic augmentation of glutamatergic neurotransmission in granule neurons that can be attributed to a release of perisynaptic GluA1-containing AMPA receptors into the postsynaptic densities of perforant pathway synapses. Furthermore, inhibiting SAP97 function in the dentate gyrus was sufficient to impair contextual episodic memory. Together, our results identify a cell-type-specific synaptic regulatory mechanism in the dentate gyrus that, when disrupted, impairs contextual information processing in rats.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Giro Denteado/fisiologia , Proteínas de Membrana/genética , Memória Episódica , Mutação , Esquizofrenia/genética , Sinapses/metabolismo , Animais , Feminino , Hipocampo/metabolismo , Masculino , Neurônios/metabolismo , Densidade Pós-Sináptica/metabolismo , Células Piramidais/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/metabolismo , Esquizofrenia/metabolismo , Transmissão Sináptica/fisiologia
12.
Schizophr Bull ; 48(3): 551-562, 2022 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-35137221

RESUMO

INTRODUCTION: Illuminating neurobiological mechanisms underlying the protective effect of recently discovered common genetic resilience variants for schizophrenia is crucial for more effective prevention efforts. Current models implicate adaptive neuroplastic changes in the visual system and their pro-cognitive effects as a schizophrenia resilience mechanism. We investigated whether common genetic resilience variants might affect brain structure in similar neural circuits. METHOD: Using structural magnetic resonance imaging, we measured the impact of an established schizophrenia polygenic resilience score (PRSResilience) on cortical volume, thickness, and surface area in 101 healthy subjects and in a replication sample of 33 224 healthy subjects (UK Biobank). FINDING: We observed a significant positive whole-brain correlation between PRSResilience and cortical volume in the right fusiform gyrus (FFG) (r = 0.35; P = .0004). Post-hoc analyses in this cluster revealed an impact of PRSResilience on cortical surface area. The replication sample showed a positive correlation between PRSResilience and global cortical volume and surface area in the left FFG. CONCLUSION: Our findings represent the first evidence of a neurobiological correlate of a genetic resilience factor for schizophrenia. They support the view that schizophrenia resilience emerges from strengthening neural circuits in the ventral visual pathway and an increased capacity for the disambiguation of social and nonsocial visual information. This may aid psychosocial functioning, ameliorate the detrimental effects of subtle perceptual and cognitive disturbances in at-risk individuals, and facilitate coping with the cognitive and psychosocial consequences of stressors. Our results thus provide a novel link between visual cognition, the vulnerability-stress concept, and schizophrenia resilience models.


Assuntos
Esquizofrenia , Encéfalo/metabolismo , Humanos , Imageamento por Ressonância Magnética , Herança Multifatorial , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/genética , Esquizofrenia/metabolismo , Vias Visuais/diagnóstico por imagem , Vias Visuais/patologia
13.
Int J Mol Sci ; 23(3)2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-35163460

RESUMO

Schizophrenia (SCZ) is a mental illness characterized by aberrant synaptic plasticity and connectivity. A large bulk of evidence suggests genetic and functional links between postsynaptic abnormalities and SCZ. Here, we performed quantitative PCR and Western blotting analysis in the dorsolateral prefrontal cortex (DLPFC) and hippocampus of SCZ patients to investigate the mRNA and protein expression of three key spine shapers: the actin-binding protein cyclase-associated protein 2 (CAP2), the sheddase a disintegrin and metalloproteinase 10 (ADAM10), and the synapse-associated protein 97 (SAP97). Our analysis of the SCZ post-mortem brain indicated increased DLG1 mRNA in DLPFC and decreased CAP2 mRNA in the hippocampus of SCZ patients, compared to non-psychiatric control subjects, while the ADAM10 transcript was unaffected. Conversely, no differences in CAP2, SAP97, and ADAM10 protein levels were detected between SCZ and control individuals in both brain regions. To assess whether DLG1 and CAP2 transcript alterations were selective for SCZ, we also measured their expression in the superior frontal gyrus of patients affected by neurodegenerative disorders, like Parkinson's and Alzheimer's disease. Interestingly, also in Parkinson's disease patients, we found a selective reduction of CAP2 mRNA levels relative to controls but unaltered protein levels. Taken together, we reported for the first time altered CAP2 expression in the brain of patients with psychiatric and neurological disorders, thus suggesting that aberrant expression of this gene may contribute to synaptic dysfunction in these neuropathologies.


Assuntos
Proteína ADAM10/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide/genética , Proteína 1 Homóloga a Discs-Large/genética , Proteínas de Membrana/genética , Doença de Parkinson/genética , Esquizofrenia/genética , Proteína ADAM10/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Autopsia , Estudos de Casos e Controles , Proteína 1 Homóloga a Discs-Large/metabolismo , Feminino , Regulação da Expressão Gênica , Hipocampo/metabolismo , Humanos , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Doença de Parkinson/metabolismo , Esquizofrenia/metabolismo
14.
Int J Mol Sci ; 23(4)2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-35216241

RESUMO

Treatment of negative symptoms and cognitive disorders in patients with schizophrenia is still a serious clinical problem. The aim of our study was to compare the efficacy of chronic administration of the atypical antipsychotic drug aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butoxy}-3,4-dihydro-2(1H)-quinolinone; ARI) and the well-known antioxidant N-acetylcysteine (NAC) both in alleviating schizophrenia-like social and cognitive deficits and in reducing the decreases in the levels of the brain-derived neurotrophic factor (BDNF) in the prefrontal cortex (PFC) and hippocampus (HIP) of adult Sprague-Dawley rats, that have been induced by chronic administration of the model compound L-buthionine-(S, R)-sulfoximine (BSO) during the early postnatal development (p5-p16). ARI was administered at doses of 0.1 and 0.3 mg/kg while NAC at doses of 10 and 30 mg/kg, alone or in combination. Administration of higher doses of ARI or NAC alone, or co-treatment with lower, ineffective doses of these drugs significantly improved social and cognitive performance as assessed in behavioral tests. Both doses of NAC and 0.3 mg/kg of ARI increased the expression of BDNF mRNA in the PFC, while all doses of these drugs and their combinations enhanced the levels of BDNF protein in this brain structure. In the HIP, only 0,3 mg/kg ARI increased the levels of both BDNF mRNA and its protein. These data show that in the rat BSO-induced neurodevelopmental model of schizophrenia, ARI and NAC differently modulated BDNF levels in the PFC and HIP.


Assuntos
Acetilcisteína/farmacologia , Aripiprazol/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Animais , Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/metabolismo , Modelos Animais de Doenças , Feminino , Hipocampo/metabolismo , Córtex Pré-Frontal/metabolismo , Gravidez , Quinolonas/farmacologia , Ratos , Ratos Sprague-Dawley , Esquizofrenia/metabolismo , Comportamento Social
15.
Neuroscience ; 490: 66-78, 2022 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-35124166

RESUMO

Schizophrenia is a neurodevelopmental disorder with dendrite and dendritic spine dysfunction. Dysbindin-1, a protein decreased in the brains of schizophrenia patients, is involved in the development of dendrites and spines. However, it is still unclear how the role of dysbindin-1 in neuronal development is regulated. Here, we showed protein kinase B/Akt1, a serine/threonine kinase implicated in schizophrenia, phosphorylated dysbindin-1A at serine 10 (S10). S10 phosphorylation of dysbindin-1A was increased during postnatal neuronal and synapse development stage, and was enriched in postsynaptic densities (PSDs). Furthermore, overexpressing wild type or S10 phospho-mimic mutant (S10D), but not S10 phospho-dead mutant (S10A) of dysbindin-1A rescued the dendrite and spine deficits in dysbindin-1A knockdown neurons. These results indicate S10 phosphorylation of dysbindin-1A by Akt1 is essential for neuronal development, providing a potential regulation mechanism for dysbindin-1A in neuronal development.


Assuntos
Proteínas Proto-Oncogênicas c-akt , Esquizofrenia , Disbindina/metabolismo , Proteínas Associadas à Distrofina , Humanos , Neurogênese , Esquizofrenia/metabolismo , Serina
16.
Genes Brain Behav ; 21(4): e12797, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35075790

RESUMO

Genetic studies implicate disruption to the DLG2 gene in copy number variants as increasing risk for schizophrenia, autism spectrum disorders and intellectual disability. To investigate psychiatric endophenotypes associated with DLG2 haploinsufficiency (and concomitant PSD-93 protein reduction) a novel clinically relevant Dlg2+/- rat was assessed for abnormalities in anxiety, sensorimotor gating, hedonic reactions, social behaviour, and locomotor response to the N-Methyl-D-aspartic acid receptor antagonist phencyclidine. Dlg gene and protein expression were also investigated to assess model validity. Reductions in PSD-93 messenger RNA and protein were observed in the absence of compensation by other related genes or proteins. Behaviourally Dlg2+/- rats show a potentiated locomotor response to phencyclidine, as is typical of psychotic disorder models, in the absence of deficits in the other behavioural phenotypes assessed here. This shows that the behavioural effects of Dlg2 haploinsufficiency may specifically relate to psychosis vulnerability but are subtle, and partially dissimilar to behavioural deficits previously reported in Dlg2+/- mouse models demonstrating issues surrounding the comparison of models with different aetiology and species. Intact performance on many of the behavioural domains assessed here, such as anxiety and reward processing, will remove these as confounds when continuing investigation into this model using more complex cognitive tasks.


Assuntos
Guanilato Quinases , Haploinsuficiência , Esquizofrenia , Proteínas Supressoras de Tumor , Animais , Modelos Animais de Doenças , Guanilato Quinases/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana , Camundongos , Fenciclidina/farmacologia , Ratos , Esquizofrenia/genética , Esquizofrenia/metabolismo , Comportamento Social , Proteínas Supressoras de Tumor/genética
17.
Int J Mol Sci ; 23(2)2022 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-35055031

RESUMO

The study aimed to examine the impact of the oropharyngeal microbiome in the pathophysiology of schizophrenia and to clarify whether there might be a bidirectional link between the oral microbiota and the brain in a context of dysbiosis-related neuroinflammation. We selected nine articles including three systemic reviews with several articles from the same research team. Different themes emerged, which we grouped into 5 distinct parts concerning the oropharyngeal phageome, the oropharyngeal microbiome, the salivary microbiome and periodontal disease potentially associated with schizophrenia, and the impact of drugs on the microbiome and schizophrenia. We pointed out the presence of phageoma in patients suffering from schizophrenia and that periodontal disease reinforces the role of inflammation in the pathophysiology of schizophrenia. Moreover, saliva could be an interesting substrate to characterize the different stages of schizophrenia. However, the few studies we have on the subject are limited in scope, and some of them are the work of a single team. At this stage of knowledge, it is difficult to conclude on the existence of a bidirectional link between the brain and the oral microbiome. Future studies on the subject will clarify these questions that for the moment remain unresolved.


Assuntos
Suscetibilidade a Doenças , Microbiota , Orofaringe/microbiologia , Esquizofrenia/etiologia , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Disbiose , Humanos , Metagenoma , Metagenômica/métodos , Microbiota/efeitos dos fármacos , /metabolismo , Doenças Periodontais/complicações , Doenças Periodontais/etiologia , Saliva/microbiologia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo
18.
Commun Biol ; 5(1): 80, 2022 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-35058554

RESUMO

Genetic correlations and an increased incidence of psychiatric disorders in inflammatory-bowel disease have been reported, but shared molecular mechanisms are unknown. We performed cross-tissue and multiple-gene conditioned transcriptome-wide association studies for 23 tissues of the gut-brain-axis using genome-wide association studies data sets (total 180,592 patients) for Crohn's disease, ulcerative colitis, primary sclerosing cholangitis, schizophrenia, bipolar disorder, major depressive disorder and attention-deficit/hyperactivity disorder. We identified NR5A2, SATB2, and PPP3CA (encoding a target for calcineurin inhibitors in refractory ulcerative colitis) as shared susceptibility genes with transcriptome-wide significance both for Crohn's disease, ulcerative colitis and schizophrenia, largely explaining fine-mapped association signals at nearby genome-wide association study susceptibility loci. Analysis of bulk and single-cell RNA-sequencing data showed that PPP3CA expression was strongest in neurons and in enteroendocrine and Paneth-like cells of the ileum, colon, and rectum, indicating a possible link to the gut-brain-axis. PPP3CA together with three further suggestive loci can be linked to calcineurin-related signaling pathways such as NFAT activation or Wnt.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Doenças Inflamatórias Intestinais/genética , Esquizofrenia/genética , Transcriptoma , /fisiologia , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Sistema de Registros , Esquizofrenia/metabolismo , Distribuição Tecidual
19.
PLoS One ; 17(1): e0262717, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35073334

RESUMO

High resolution in situ hybridization (ISH) images of the brain capture spatial gene expression at cellular resolution. These spatial profiles are key to understanding brain organization at the molecular level. Previously, manual qualitative scoring and informatics pipelines have been applied to ISH images to determine expression intensity and pattern. To better capture the complex patterns of gene expression in the human cerebral cortex, we applied a machine learning approach. We propose gene re-identification as a contrastive learning task to compute representations of ISH images. We train our model on an ISH dataset of ~1,000 genes obtained from postmortem samples from 42 individuals. This model reaches a gene re-identification rate of 38.3%, a 13x improvement over random chance. We find that the learned embeddings predict expression intensity and pattern. To test generalization, we generated embeddings in a second dataset that assayed the expression of 78 genes in 53 individuals. In this set of images, 60.2% of genes are re-identified, suggesting the model is robust. Importantly, this dataset assayed expression in individuals diagnosed with schizophrenia. Gene and donor-specific embeddings from the model predict schizophrenia diagnosis at levels similar to that reached with demographic information. Mutations in the most discriminative gene, Sodium Voltage-Gated Channel Beta Subunit 4 (SCN4B), may help understand cardiovascular associations with schizophrenia and its treatment. We have publicly released our source code, embeddings, and models to spur further application to spatial transcriptomics. In summary, we propose and evaluate gene re-identification as a machine learning task to represent ISH gene expression images.


Assuntos
Interpretação de Imagem Assistida por Computador/métodos , Hibridização In Situ/métodos , Redes Neurais de Computação , Transcriptoma , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Estudos de Casos e Controles , Conjuntos de Dados como Assunto , Feminino , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/metabolismo , Esquizofrenia/patologia , Adulto Jovem
20.
Mol Psychiatry ; 27(1): 744-757, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34584230

RESUMO

BACKGROUND: The glutamate (Glu) and gamma aminobutyric acid (GABA) hypotheses of schizophrenia were proposed in the 1980s. However, current findings on those metabolite levels in schizophrenia have been inconsistent, and the relationship between their abnormalities and the pathophysiology of schizophrenia remains unclear. To summarize the nature of the alterations of glutamatergic and GABAergic systems in schizophrenia, we conducted meta-analyses of proton magnetic resonance spectroscopy (1H-MRS) studies examining these metabolite levels. METHODS: A systematic literature search was conducted using Embase, Medline, PsycINFO, and PubMed. Original studies that compared four metabolite levels (Glu, glutamine [Gln], Glx [Glu+Gln], and GABA), as measured by 1H-MRS, between individuals at high risk for psychosis, patients with first-episode psychosis, or patients with schizophrenia and healthy controls (HC) were included. A random-effects model was used to calculate the effect sizes for group differences in these metabolite levels of 18 regions of interest between the whole group or schizophrenia group and HC. Subgroup analysis and meta-regression were performed based on the status of antipsychotic treatment, illness stage, treatment resistance, and magnetic field strength. RESULTS: One-hundred-thirty-four studies met the eligibility criteria, totaling 7993 participants with SZ-spectrum disorders and 8744 HC. 14 out of 18 ROIs had enough numbers of studies to examine the group difference in the metabolite levels. In the whole group, Glx levels in the basal ganglia (g = 0.32; 95% CIs: 0.18-0.45) were elevated. Subgroup analyses showed elevated Glx levels in the hippocampus (g = 0.47; 95% CIs: 0.21-0.73) and dorsolateral prefrontal cortex (g = 0.25; 95% CIs: 0.05-0.44) in unmedicated patients than HC. GABA levels in the MCC were decreased in the first-episode psychosis group compared with HC (g = -0.40; 95% CIs: -0.62 to -0.17). Treatment-resistant schizophrenia (TRS) group had elevated Glx and Glu levels in the MCC (Glx: g = 0.7; 95% CIs: 0.38-1.01; Glu: g = 0.63; 95% CIs: 0.31-0.94) while MCC Glu levels were decreased in the patient group except TRS (g = -0.17; 95% CIs: -0.33 to -0.01). CONCLUSIONS: Increased glutamatergic metabolite levels and reduced GABA levels indicate that the disruption of excitatory/inhibitory balance may be related to the pathophysiology of schizophrenia-spectrum disorders.


Assuntos
Esquizofrenia , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Humanos , Espectroscopia de Ressonância Magnética , Espectroscopia de Prótons por Ressonância Magnética/métodos , Esquizofrenia/metabolismo , Ácido gama-Aminobutírico/metabolismo
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