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1.
Immunity ; 54(11): 2611-2631.e8, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34758338

RESUMO

Early prenatal inflammatory conditions are thought to be a risk factor for different neurodevelopmental disorders. Maternal interleukin-6 (IL-6) elevation during pregnancy causes abnormal behavior in offspring, but whether these defects result from altered synaptic developmental trajectories remains unclear. Here we showed that transient IL-6 elevation via injection into pregnant mice or developing embryos enhanced glutamatergic synapses and led to overall brain hyperconnectivity in offspring into adulthood. IL-6 activated synaptogenesis gene programs in glutamatergic neurons and required the transcription factor STAT3 and expression of the RGS4 gene. The STAT3-RGS4 pathway was also activated in neonatal brains during poly(I:C)-induced maternal immune activation, which mimics viral infection during pregnancy. These findings indicate that IL-6 elevation at early developmental stages is sufficient to exert a long-lasting effect on glutamatergic synaptogenesis and brain connectivity, providing a mechanistic framework for the association between prenatal inflammatory events and brain neurodevelopmental disorders.


Assuntos
Hipocampo/metabolismo , Interleucina-6/biossíntese , Exposição Materna , Neurônios/metabolismo , Efeitos Tardios da Exposição Pré-Natal , Sinapses/metabolismo , Animais , Citocinas/biossíntese , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Hipocampo/fisiopatologia , Mediadores da Inflamação/metabolismo , Camundongos , Gravidez , Transdução de Sinais , Transmissão Sináptica
2.
EMBO J ; 41(23): e111192, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36314682

RESUMO

Intracerebral hemorrhages are recognized risk factors for neurodevelopmental disorders and represent early biomarkers for cognitive dysfunction and mental disability, but the pathways leading to their occurrence are not well defined. We report that a single intrauterine exposure of the immunostimulant Poly I:C to pregnant mice at gestational day 9, which models a prenatal viral infection and the consequent maternal immune activation, induces the defective formation of brain vessels and causes intracerebral hemorrhagic events, specifically in male offspring. We demonstrate that maternal immune activation promotes the production of the TGF-ß1 active form and the consequent enhancement of pSMAD1-5 in males' brain endothelial cells. TGF-ß1, in combination with IL-1ß, reduces the endothelial expression of CD146 and claudin-5, alters the endothelium-pericyte interplay resulting in low pericyte coverage, and increases hemorrhagic events in the adult offspring. By showing that exposure to Poly I:C at the beginning of fetal cerebral angiogenesis results in sex-specific alterations of brain vessels, we provide a mechanistic framework for the association between intragravidic infections and anomalies of the neural vasculature, which may contribute to neuropsychiatric disorders.


Assuntos
Hemorragia Cerebral , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Masculino , Camundongos , Gravidez , Comportamento Animal , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Hemorragia Cerebral/patologia , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Poli I-C/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/patologia , Fator de Crescimento Transformador beta1/metabolismo
3.
EMBO J ; 38(1)2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30396995

RESUMO

Control of synapse number and function in the developing central nervous system is critical to the formation of neural circuits. Astrocytes play a key role in this process by releasing factors that promote the formation of excitatory synapses. Astrocyte-secreted thrombospondins (TSPs) induce the formation of structural synapses, which however remain post-synaptically silent, suggesting that completion of early synaptogenesis may require a two-step mechanism. Here, we show that the humoral innate immune molecule Pentraxin 3 (PTX3) is expressed in the developing rodent brain. PTX3 plays a key role in promoting functionally-active CNS synapses, by increasing the surface levels and synaptic clustering of AMPA glutamate receptors. This process involves tumor necrosis factor-induced protein 6 (TSG6), remodeling of the perineuronal network, and a ß1-integrin/ERK pathway. Furthermore, PTX3 activity is regulated by TSP1, which directly interacts with the N-terminal region of PTX3. These data unveil a fundamental role of PTX3 in promoting the first wave of synaptogenesis, and show that interplay of TSP1 and PTX3 sets the proper balance between synaptic growth and synapse function in the developing brain.


Assuntos
Proteína C-Reativa/fisiologia , Matriz Extracelular/metabolismo , Integrina beta1/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Receptores de AMPA/metabolismo , Sinapses/fisiologia , Animais , Astrócitos/metabolismo , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Proteína C-Reativa/genética , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Matriz Extracelular/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Plasticidade Neuronal/genética , Transporte Proteico/genética , Trombospondina 1/metabolismo
5.
J Clin Invest ; 134(14)2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39007270

RESUMO

Copy number variation (CNV) at 7q11.23 causes Williams-Beuren syndrome (WBS) and 7q microduplication syndrome (7Dup), neurodevelopmental disorders (NDDs) featuring intellectual disability accompanied by symmetrically opposite neurocognitive features. Although significant progress has been made in understanding the molecular mechanisms underlying 7q11.23-related pathophysiology, the propagation of CNV dosage across gene expression layers and their interplay remains elusive. Here we uncovered 7q11.23 dosage-dependent symmetrically opposite dynamics in neuronal differentiation and intrinsic excitability. By integrating transcriptomics, translatomics, and proteomics of patient-derived and isogenic induced neurons, we found that genes related to neuronal transmission follow 7q11.23 dosage and are transcriptionally controlled, while translational factors and ribosomal genes are posttranscriptionally buffered. Consistently, we found phosphorylated RPS6 (p-RPS6) downregulated in WBS and upregulated in 7Dup. Surprisingly, p-4EBP was changed in the opposite direction, reflecting dosage-specific changes in total 4EBP levels. This highlights different dosage-sensitive dyregulations of the mTOR pathway as well as distinct roles of p-RPS6 and p-4EBP during neurogenesis. Our work demonstrates the importance of multiscale disease modeling across molecular and functional layers, uncovers the pathophysiological relevance of ribosomal biogenesis in a paradigmatic pair of NDDs, and uncouples the roles of p-RPS6 and p-4EBP as mechanistically actionable relays in NDDs.


Assuntos
Cromossomos Humanos Par 7 , Variações do Número de Cópias de DNA , Neurônios , Humanos , Neurônios/metabolismo , Neurônios/patologia , Cromossomos Humanos Par 7/genética , Ribossomos/metabolismo , Ribossomos/genética , Neurogênese/genética , Síndrome de Williams/genética , Síndrome de Williams/metabolismo , Síndrome de Williams/patologia , Síndrome de Williams/fisiopatologia , Proteína S6 Ribossômica/metabolismo , Proteína S6 Ribossômica/genética , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/genética , Masculino , Diferenciação Celular , Feminino
6.
NPJ Genom Med ; 8(1): 28, 2023 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-37770509

RESUMO

Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME (n = 381). Results were followed up with functional characterisation using a drosophila model. We identified genome-wide associated SNPs at 8q13.3 (P = 7.5 × 10-9) and 10p11.21 (P = 3.6 × 10-8). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (P = 9.5 × 10-3). SLCO5A1 codes for an organic anion transporter and upregulates synapse assembly/organisation genes. Pathway analysis demonstrates 12.7-fold enrichment for presynaptic membrane assembly genes (P = 0.0005) and 14.3-fold enrichment for presynaptic organisation genes (P = 0.0005) including NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila polypeptide with the highest homology to SLCO5A1, causes over-reactive startling behaviour (P = 8.7 × 10-3) and increased seizure-like events (P = 6.8 × 10-7). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (P = 1.60 × 10-3). SLCO5A1 loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease.

7.
FEBS J ; 289(12): 3374-3392, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-33998773

RESUMO

Intragravidic and perinatal infections, acting through either direct viral effect or immune-mediated responses, are recognized causes of liability for neurodevelopmental disorders in the progeny. The large amounts of epidemiological data and the wealth of information deriving from animal models of gestational infections have contributed to delineate, in the last years, possible underpinning mechanisms for this phenomenon, including defects in neuronal migration, impaired spine and synaptic development, and altered activation of microglia. Recently, dysfunctions of the neurovascular unit and anomalies of the brain vasculature have unexpectedly emerged as potential causes at the origin of behavioral abnormalities and psychiatric disorders consequent to prenatal and perinatal infections. This review aims to discuss the up-to-date literature evidence pointing to the neurovascular unit and brain vasculature damages as the etiological mechanisms in neurodevelopmental syndromes. We focus on the inflammatory events consequent to intragravidic viral infections as well as on the direct viral effects as the potential primary triggers. These authors hope that a timely review of the literature will help to envision promising research directions, also relevant for the present and future COVID-19 longitudinal studies.


Assuntos
COVID-19 , Transtornos Mentais , Complicações Infecciosas na Gravidez , Efeitos Tardios da Exposição Pré-Natal , Animais , Encéfalo , Feminino , Humanos , Gravidez
8.
EMBO Mol Med ; 13(4): e12433, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33665914

RESUMO

MECP2 mutations cause Rett syndrome (RTT), a severe and progressive neurodevelopmental disorder mainly affecting females. Although RTT patients exhibit delayed onset of symptoms, several evidences demonstrate that MeCP2 deficiency alters early development of the brain. Indeed, during early maturation, Mecp2 null cortical neurons display widespread transcriptional changes, reduced activity, and defective morphology. It has been proposed that during brain development these elements are linked in a feed-forward cycle where neuronal activity drives transcriptional and morphological changes that further increase network maturity. We hypothesized that the enhancement of neuronal activity during early maturation might prevent the onset of RTT-typical molecular and cellular phenotypes. Accordingly, we show that the enhancement of excitability, obtained by adding to neuronal cultures Ampakine CX546, rescues transcription of several genes, neuronal morphology, and responsiveness to stimuli. Greater effects are achieved in response to earlier treatments. In vivo, short and early administration of CX546 to Mecp2 null mice prolongs lifespan, delays the disease progression, and rescues motor abilities and spatial memory, thus confirming the value for RTT of an early restoration of neuronal activity.


Assuntos
Proteína 2 de Ligação a Metil-CpG , Síndrome de Rett , Animais , Encéfalo/metabolismo , Feminino , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/metabolismo , Camundongos , Neurônios/metabolismo , Fenótipo , Síndrome de Rett/genética
9.
eNeuro ; 7(4)2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719102

RESUMO

Posttranslational modifications (PTMs) represent a dynamic regulatory system that precisely modulates the functional organization of synapses. PTMs consist in target modifications by small chemical moieties or conjugation of lipids, sugars or polypeptides. Among them, ubiquitin and a large family of ubiquitin-like proteins (UBLs) share several features such as the structure of the small protein modifiers, the enzymatic cascades mediating the conjugation process, and the targeted aminoacidic residue. In the brain, ubiquitination and two UBLs, namely sumoylation and the recently discovered neddylation orchestrate fundamental processes including synapse formation, maturation and plasticity, and their alteration is thought to contribute to the development of neurological disorders. Remarkably, emerging evidence suggests that these pathways tightly interplay to modulate the function of several proteins that possess pivotal roles for brain homeostasis as well as failure of this crosstalk seems to be implicated in the development of brain pathologies. In this review, we outline the role of ubiquitination, sumoylation, neddylation, and their functional interplay in synapse physiology and discuss their implication in the molecular pathogenesis of intellectual disability (ID), a neurodevelopmental disorder that is frequently comorbid with a wide spectrum of brain pathologies. Finally, we propose a few outlooks that might contribute to better understand the complexity of these regulatory systems in regard to neuronal circuit pathophysiology.


Assuntos
Deficiência Intelectual , Ubiquitina , Humanos , Sumoilação , Sinapses/metabolismo , Ubiquitinas/metabolismo
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