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1.
Acta Psychiatr Scand ; 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33524175

RESUMO

OBJECTIVE: Psychotic experiences, such as hallucinations, occur commonly in children and have been related to bullying victimization. However, whether bullying perpetration, peer rejection, or peer acceptance are related to hallucinatory experiences has remained under-examined. We used a novel peer nomination method to examine whether (i) bullying perpetration and (ii) social positions within peer networks were associated with future hallucinatory experiences. METHODS: This prospective study was embedded in the population-based Generation R Study. Bullying perpetration, peer rejection, and peer acceptance were assessed using peer nominations at age 7 years (N = 925). Using a social network analysis, we estimated social positions within peer rejection and acceptance networks. Bullying victimization was assessed using self-reports. Self-reported hallucinatory experiences were assessed at age 10 years. Analyses were adjusted for sociodemographic covariates. RESULTS: Higher levels of bullying perpetration were prospectively associated with an increased burden of hallucinatory experiences (OR = 1.22, 95% CI 1.05-1.43, p = 0.011). Bullies had a 50% higher, and bully-victims had a 89% higher odds, of endorsing hallucinatory experiences three years later than children who were not involved in bullying (ORbully = 1.50, 95% CI 1.01-2.24, p = 0.045; ORbully-victim = 1.89, 95% CI 1.15-3.10, p = 0.012). Unfavorable positions within peer rejection networks, but not peer acceptance networks, were associated with an increased risk for hallucinatory experiences (ORpeer rejection = 1.24, 95% CI 1.07-1.44, pFDR-corrected = 0.024). CONCLUSION: Using peer reports, we observed that bullies and socially rejected children have a higher likelihood to report hallucinatory experiences in pre-adolescence. Children who are both a bully and a victim of bullying (ie, bully-victims) may be particularly vulnerable for psychotic experiences.

2.
Ann Neurol ; 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33527515

RESUMO

OBJECTIVE: Perinatal intracranial hemorrhage (pICH) is a rare event that occurs during the fetal/neonatal period with potentially devastating neurological outcome. However, the etiology of pICH is frequently hard to depict. We investigated the role of rare genetic variations in unexplained cases of pICH. METHODS: We performed whole-exome sequencing (WES) in fetuses and term neonates with otherwise unexplained pICH and their parents. Variant causality was determined according to the American College of Medical Genetics and Genomics (ACMG) criteria, consistency between suggested genes and phenotypes, and mode of inheritance. RESULTS: Twenty-six probands (25 families) were included in the study (9 with a prenatal diagnosis and 17 with a postnatal diagnosis). Intraventricular hemorrhage (IVH) was the most common type of hemorrhage (n = 16, 62%), followed by subpial (n = 4, 15%), subdural (n = 4, 15%), and parenchymal (n = 2, 8%) hemorrhage. Causative/likely causative variants were found in 4 subjects from 3 of the 25 families (12%) involving genes related to the brain microenvironment (COL4A1, COL4A2, and TREX-1). Additionally, potentially causative variants were detected in genes related to coagulation (GP1BA, F11, Von Willebrand factor [VWF], FGA, and F7; n = 4, 16%). A potential candidate gene for phenotypic expansion related to microtubular function (DNAH5) was identified in 1 case (4%). Fifty-five percent of the variants were inherited from an asymptomatic parent. Overall, these findings showed a monogenic cause for pICH in 12% to 32% of the families. INTERPRETATION: Our findings reveal a clinically significant diagnostic yield of WES in apparently idiopathic pICH and support the use of WES in the evaluation of these cases. ANN NEUROL 2021.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33635441

RESUMO

Previous studies have shown that schizophrenia polygenic risk predicts a multitude of mental health problems in the general population. Yet it is unclear by which mechanisms these associations arise. Here, we explored a possible gene-environment correlation in the association of schizophrenia polygenic risk with mental health problems via childhood adversity. This study was embedded in the population-based Generation R Study, including N = 1901 participants with genotyping for schizophrenia polygenic risk, maternal reporting of childhood adversity, and Child Behaviour Checklist measurement of mental health problems. Independent replication was attempted in the Avon Longitudinal Study of Parents and Children (ALSPAC; N = 3641). Associations were analysed with Poisson regression and statistical mediation analysis. Higher burden of schizophrenia polygenic risk was associated with greater exposure to childhood adversity (P-value threshold < 0.5: Generation R Study, OR = 1.08, 95%CI 1.02-1.15, P = 0.01; ALSPAC, OR = 1.02, 95%CI 1.01-1.03, P < 0.01). Childhood adversities partly explained the relationship of schizophrenia polygenic risk with emotional, attention, and thought problems (proportion explained, range 5-23%). Direct effects of schizophrenia polygenic risk and adversity on mental health outcomes were also observed. In summary, genetic liability to schizophrenia increased the risk for mental health problems in the general paediatric population through childhood adversity. Although this finding could result from a mediated causal relationship between genotype and mental health, we argue that these observations most likely reflect a gene-environment correlation, i.e. adversities are a marker for the genetic risk that parents transmit to children. These and similar recent findings raise important conceptual questions about preventative interventions aimed at reducing childhood adversities.

4.
Hum Mol Genet ; 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33555315

RESUMO

Oligodendrocytes exist in a heterogenous state and are implicated in multiple neuropsychiatric diseases including dementia. Cortical oligodendrocytes are a glial population uniquely positioned to play a key role in neurodegeneration by synchronizing circuit connectivity but molecular pathways specific to this role are lacking. We utilized oligodendrocyte-specific translating ribosome affinity purification and RNA-seq (TRAP-seq) to transcriptionally profile adult mature oligodendrocytes from different regions of the central nervous system. Weighted gene co-expression network analysis (WGCNA) reveals distinct region-specific gene networks. Two of these mature myelinating oligodendrocyte gene networks uniquely define cortical oligodendrocytes and differentially regulate cortical myelination (M8) and synaptic signaling (M4). These two cortical oligodendrocyte gene networks are enriched for genes associated with dementia including MAPT and include multiple gene targets of the regulatory microRNA, miR-142-3p. Using a combination of TRAP-qPCR, miR-142-3p overexpression in vitro, and miR-142-null mice, we show that miR-142-3p negatively regulates cortical myelination. In rTg4510 tau-overexpressing mice, cortical myelination is compromised, and tau-mediated neurodegeneration is associated with gene co-expression networks that recapitulate both the M8 and M4 cortical oligodendrocyte gene networks identified from normal cortex. We further demonstrate overlapping gene networks in mature oligodendrocytes present in normal cortex, rTg4510 and miR-142-null mice, and existing datasets from human tauopathies to provide evidence for a critical role of miR-142-3p-regulated cortical myelination and oligodendrocyte-mediated synaptic signaling in neurodegeneration.

6.
Hum Mol Genet ; 29(18): 3032-3043, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-32879944

RESUMO

The human UBE3A gene, which is essential for normal neurodevelopment, encodes three Ubiquitin E3 ligase A (UBE3A) protein isoforms. However, the subcellular localization and relative abundance of these human UBE3A isoforms are unknown. We found, as previously reported in mice, that UBE3A is predominantly nuclear in human neurons. However, this conserved subcellular distribution is achieved by strikingly distinct cis-acting mechanisms. A single amino-acid deletion in the N-terminus of human hUBE3A-Iso3, which is homologous to cytosolic mouse mUBE3A-Iso2, results in its translocation to the nucleus. This singe amino-acid deletion is shared with apes and Old World monkeys and was preceded by the appearance of the cytosolic hUBE3A-Iso2 isoform. This hUBE3A-Iso2 isoform arose after the lineage of New World monkeys and Old World monkeys separated from the Tarsiers (Tarsiidae). Due to the loss of a single nucleotide in a non-coding exon, this exon became in frame with the remainder of the UBE3A protein. RNA-seq analysis of human brain samples showed that the human UBE3A isoforms arise by alternative splicing. Consistent with the predominant nuclear enrichment of UBE3A in human neurons, the two nuclear-localized isoforms, hUBE3A-Iso1 and -Iso3, are the most abundantly expressed isoforms of UBE3A, while hUBE3A-Iso2 maintains a small pool of cytosolic UBE3A. Our findings provide new insight into UBE3A localization and evolution and may have important implications for gene therapy approaches in Angelman syndrome.

7.
Curr Biol ; 30(18): R1014-R1018, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32961149

RESUMO

Recently, a petition was offered to the European Commission calling for an immediate ban on animal testing. Although a Europe-wide moratorium on the use of animals in science is not yet possible, there has been a push by the non-scientific community and politicians for a rapid transition to animal-free innovations. Although there are benefits for both animal welfare and researchers, advances on alternative methods have not progressed enough to be able to replace animal research in the foreseeable future. This trend has led first and foremost to a substantial increase in the administrative burden and hurdles required to make timely advances in research and treatments for human and animal diseases. The current COVID-19 pandemic clearly highlights how much we actually rely on animal research. COVID-19 affects several organs and systems, and the various animal-free alternatives currently available do not come close to this complexity. In this Essay, we therefore argue that the use of animals is essential for the advancement of human and veterinary health.


Assuntos
Experimentação Animal , Pesquisa Biomédica , Infecções por Coronavirus , Modelos Animais de Doenças , Pandemias , Pneumonia Viral , Animais , Betacoronavirus , Humanos
8.
Clin Neurophysiol ; 131(11): 2673-2681, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32977190

RESUMO

OBJECTIVE: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder that is associated with cognitive disabilities. Based on studies involving animals, the hypothesized cause of these disabilities results from increased activity of inhibitory interneurons that decreases synaptic plasticity. We obtained transcranial magnetic stimulation (TMS)-based measures of cortical inhibition, excitability and plasticity in individuals with NF1. METHODS: We included 32 NF1 adults and 32 neurotypical controls. Cortical inhibition was measured with short-interval intracortical inhibition (SICI) and cortical silent period (CSP). Excitability and plasticity were studied with intermittent theta burst stimulation (iTBS). RESULTS: The SICI and CSP response did not differ between NF1 adults and controls. The response upon iTBS induction was significantly increased in controls (70%) and in NF1 adults (83%). This potentiation lasted longer in controls than in individuals with NF1. Overall, the TMS response was significantly lower in NF1 patients (F(1, 41) = 7.552, p = 0.009). CONCLUSIONS: Individuals with NF1 may have reduced excitability and plasticity, as indicated by their lower TMS response and attenuation of the initial potentiated response upon iTBS induction. However, our findings did not provide evidence for increased inhibition in NF1 patients. SIGNIFICANCE: These findings have potential utility as neurophysiological outcome measures for intervention studies to treat cognitive deficits associated with NF1.

9.
JAMA Pediatr ; 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32955580

RESUMO

Importance: Preterm and postterm births are associated with adverse neuropsychiatric outcomes. However, it remains unclear whether variation of gestational age within the 37- to 42-week range of term deliveries is associated with neurodevelopment. Objective: To investigate the association of gestational age at birth (GAB) with structural brain morphometry in children aged 10 years. Design, Setting, and Participants: This population-based cohort study included pregnant women living in Rotterdam, the Netherlands, with an expected delivery date between April 1, 2002, and January 31, 2006. The study evaluated 3079 singleton children with GAB ranging from 26.3 to 43.3 weeks and structural neuroimaging at 10 years of age from the Generation R Study, a longitudinal, population-based prospective birth cohort from early pregnancy onward in Rotterdam. Data analysis was performed from March 1, 2019, to February 28, 2020, and at the time of the revision based on reviewer suggestions. Exposures: The GAB was calculated based on ultrasonographic assessment of crown-rump length (<12 weeks 5 days) or biparietal diameter (≥12 weeks 5 days) in dedicated research centers. Main Outcomes and Measures: Brain structure, including global and regional brain volumes and surface-based cortical measures (thickness, surface area, and gyrification), was quantified by magnetic resonance imaging. Results: In the 3079 children (1546 [50.2%] female) evaluated at 10 years of age, GAB was linearly associated with global and regional brain volumes. Longer gestational duration was associated with larger brain volumes; for example, every 1-week-longer gestational duration corresponded to an additional 4.5 cm3/wk (95% CI, 2.7-6.3 cm3/wk) larger total brain volume. These associations persisted when the sample was restricted to children born at term (GAB of 37-42 weeks: 4.8 cm3/wk; 95% CI, 1.8-7.7 cm3/wk). No evidence of nonlinear associations between GA and brain morphometry was observed. Conclusions and Relevance: In this cohort study, gestational duration was linearly associated with brain morphometry during childhood, including within the window of term delivery. These findings may have marked clinical importance, particularly given the prevalence of elective cesarean deliveries.

10.
Artigo em Inglês | MEDLINE | ID: mdl-32559319

RESUMO

BACKGROUND: Psychotic experiences are common in childhood and an important risk indicator of adverse mental health outcomes. However, little is known about the association of psychotic experiences with functional outcomes in childhood, particularly regarding school performance. The aim of the present study was to examine whether psychotic experiences were prospectively related to school performance in childhood. METHODS: This study was embedded in the population-based Generation R Study (N = 2,362). Psychotic experiences were assessed using self-reports on hallucinations at age 10 years. School performance was assessed using a standardized national school performance test at age 12 years. We considered the total school performance score, as well as language and mathematics subscales. Analyses were adjusted for sociodemographic characteristics, maternal nonverbal IQ, nonverbal IQ at age 6 years and co-occurring psychopathology at age 10 years. RESULTS: Psychotic experiences were prospectively associated with poorer school performance scores (B = -0.61, 95% CI [-0.98;-0.25], p = .001), as well as poorer language (Bpercentile rank score  = -2.00, 95% CI [-3.20;-0.79], p = .001) and mathematical ability (Bpercentile rank score  = -1.75, 95% CI [-2.99;-0.51], p = .006). These associations remained after additional adjustment for nonverbal IQ at age 6 years (B = -0.51, 95% CI [-0.86;-0.16], p = .005), and co-occurring internalizing (B = -0.40, 95% CI [-0.77;-0.03], p = .036) and externalizing problems (B = -0.40, 95% CI [-0.75;-0.04], p = .029), but not attention problems (B = -0.10, 95% CI [-0.47;0.26], p = .57). CONCLUSIONS: Children with psychotic experiences had lower school performance scores than their nonaffected peers. The finding was independent of sociodemographic characteristics, intelligence and co-occurring internalizing and externalizing problems, but not attention problems. This study suggests that psychotic experiences are associated with childhood functional impairments, although the relatively small effects and the role of attention problems warrant further exploration.

11.
Genes Brain Behav ; 19(6): e12656, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32383552

RESUMO

It remains unclear whether the genetic risk for late-onset Alzheimer disease (AD) is linked to premorbid individual differences in general cognitive ability and brain structure. The objective of the present study was to determine whether the genetic risk of late-onset AD is related to premorbid individual differences in intelligence quotient (IQ) and characteristics of the cerebral white-matter in children. The study sample included children of the Generation R Study from Rotterdam, The Netherlands. IQ was measured using a well-validated Dutch nonverbal IQ test (n = 1908) at ages 5 to 9 years. White-matter microstructure was assessed by measuring fractional anisotropy (FA) of white-matter tracts using diffusion tensor imaging (DTI) (n = 919) at ages 9 to 12 years. Genetic risk was quantified using three biologically defined genetic risk scores (GRSs) hypothesized to be related to the pathophysiology of late-onset AD: immune response, cholesterol/lipid metabolism and endocytosis. Higher genetic risk for late-onset AD that included genes associated with immune responsivity had a negative influence on cognition and cerebral white-matter microstructure. For each unit increase in the immune response GRS, IQ decreased by 0.259 SD (95% CI [-0.500, -0.017]). For each unit increase in the immune response GRS, global FA decreased by 0.373 SD (95% CI [-0.721, -0.026]). Neither cholesterol/lipid metabolism nor endocytosis GRSs were associated with IQ or cerebral white-matter microstructure. Our findings suggest that elevated genetic risk for late-onset AD may in part be manifest during childhood neurodevelopment through alterations in immune responsivity.

12.
Hum Genet ; 139(11): 1381-1390, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32399599

RESUMO

Developmental disorders (DD), characterized by malformations/dysmorphism and/or intellectual disability, affecting around 3% of worldwide population, are mostly linked to genetic anomalies. Despite clinical exome sequencing (cES) centered on genes involved in human genetic disorders, the majority of patients affected by DD remain undiagnosed after solo-cES. Trio-based strategy is expected to facilitate variant selection thanks to rapid parental segregation. We performed a second step trio-ES (not only focusing on genes involved in human disorders) analysis in 70 patients with negative results after solo-cES. All candidate variants were shared with a MatchMaking exchange system to identify additional patients carrying variants in the same genes and with similar phenotype. In 18/70 patients (26%), we confirmed causal implication of nine OMIM-morbid genes and identified nine new strong candidate genes (eight de novo and one compound heterozygous variants). These nine new candidate genes were validated through the identification of patients with similar phenotype and genotype thanks to data sharing. Moreover, 11 genes harbored variants of unknown significance in 10/70 patients (14%). In DD, a second step trio-based ES analysis appears an efficient strategy in diagnostic and translational research to identify highly candidate genes and improve diagnostic yield.


Assuntos
Deficiências do Desenvolvimento/genética , Exoma/genética , Predisposição Genética para Doença/genética , Deficiência Intelectual/genética , Feminino , Genômica/métodos , Humanos , Masculino , Fenótipo , Sequenciamento Completo do Exoma/métodos
13.
J Clin Psychiatry ; 81(2)2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32160423

RESUMO

OBJECTIVE: There is limited information on the longitudinal disease course after first-onset postpartum psychosis (PP). Some women will experience severe affective episodes outside the postpartum period, while for other women their vulnerability to mania and psychosis may be restricted to the postpartum period. This meta-analysis estimates the risk of recurrence after first-onset PP. DATA SOURCES: A computerized literature search was conducted using Embase, MEDLINE, Web of Science, PsycINFO, Cochrane Central, PubMed, and Google Scholar (first 100 hits) combining key terms regarding longitudinal studies of first-onset PP from inception through May 9, 2019. Two levels of screening were used on 2,807 citations. STUDY SELECTION: A total of 6 English-language articles including patients with a first-onset PP within 1 year after childbirth and a minimum follow-up period of 18 months or more after the index episode were included in the quantitative analysis. DATA EXTRACTION: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines were used for data extraction, and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were used to independently assess the quality of the included studies. The primary outcome was recurrence, defined as any subsequent psychiatric episode after first-onset PP. RESULTS: Six studies and 645 patients could be included in the quantitative analyses; follow-up periods were 11-26 years. Of these patients, 279 did not experience subsequent severe episodes outside the postpartum period. Meta-analysis using random-effect estimation resulted in a weighted estimate of 43.5% (95% CI, 37.7% to 49.4%). CONCLUSIONS: In this meta-analysis, more than 40% of women were classified as having "isolated postpartum psychosis," which could be considered a distinct diagnostic category with a more favorable prognosis. The remaining women had severe non-puerperal psychiatric episodes during longitudinal follow-up.


Assuntos
Progressão da Doença , Período Pós-Parto , Transtornos Psicóticos , Transtornos Puerperais , Feminino , Humanos , Recidiva
14.
Adv Healthc Mater ; 9(4): e1901347, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31943855

RESUMO

Substrates for neuron culture and implantation are required to be both biocompatible and display surface compositions that support cell attachment, growth, differentiation, and neural activity. Laminin, a naturally occurring extracellular matrix protein is the most widely used substrate for neuron culture and fulfills some of these requirements, however, it is expensive, unstable (compared to synthetic materials), and prone to batch-to-batch variation. This study uses a high-throughput polymer screening approach to identify synthetic polymers that supports the in vitro culture of primary mouse cerebellar neurons. This allows the identification of materials that enable primary cell attachment with high viability even under "serum-free" conditions, with materials that support both primary cells and neural progenitor cell attachment with high levels of neuronal biomarker expression, while promoting progenitor cell maturation to neurons.

15.
Hum Mutat ; 41(2): 476-486, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31692205

RESUMO

We describe the underlying genetic cause of a novel Rett-like phenotype accompanied by areflexia in three methyl-CpG-binding protein 2-negative individuals from two unrelated families. Discovery analysis was performed using whole-exome sequencing followed by Sanger sequencing for validation and segregation. Functional studies using short-hairpin RNA for targeted gene knockdown were implemented by the transfection of mouse cultured primary hippocampal neurons and in vivo by in utero electroporation. All patients shared a common homozygous frameshift mutation (chr9:135073515, c.376dupT, p.(Ser126PhefsTer241)) in netrin-G2 (NTNG2, NM_032536.3) with predicted nonsense-mediated decay. The mutation fully segregated with the disease in both families. The knockdown of either NTNG2 or the related netrin-G family member NTNG1 resulted in severe neurodevelopmental defects of neuronal morphology and migration. While NTNG1 has previously been linked to a Rett syndrome (RTT)-like phenotype, this is the first description of a RTT-like phenotype caused by NTNG2 mutation. Netrin-G proteins have been shown to be required for proper axonal guidance during early brain development and involved in N-methyl- d-aspartate-mediated synaptic transmission. Our results demonstrating that knockdown of murine NTNG2 causes severe impairments of neuronal morphology and cortical migration are consistent with those of RTT animal models and the shared neurodevelopmental phenotypes between the individuals described here and typical RTT patients.

16.
Elife ; 82019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31763980

RESUMO

The human face represents a combined set of highly heritable phenotypes, but knowledge on its genetic architecture remains limited, despite the relevance for various fields. A series of genome-wide association studies on 78 facial shape phenotypes quantified from 3-dimensional facial images of 10,115 Europeans identified 24 genetic loci reaching study-wide suggestive association (p < 5 × 10-8), among which 17 were previously unreported. A follow-up multi-ethnic study in additional 7917 individuals confirmed 10 loci including six unreported ones (padjusted < 2.1 × 10-3). A global map of derived polygenic face scores assembled facial features in major continental groups consistent with anthropological knowledge. Analyses of epigenomic datasets from cranial neural crest cells revealed abundant cis-regulatory activities at the face-associated genetic loci. Luciferase reporter assays in neural crest progenitor cells highlighted enhancer activities of several face-associated DNA variants. These results substantially advance our understanding of the genetic basis underlying human facial variation and provide candidates for future in-vivo functional studies.


Assuntos
Face/anatomia & histologia , Loci Gênicos/genética , Desenvolvimento Maxilofacial/genética , Fenótipo , Adolescente , Adulto , Pontos de Referência Anatômicos , Padronização Corporal/genética , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Ontologia Genética , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Imageamento Tridimensional , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Adulto Jovem
17.
Elife ; 82019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31742557

RESUMO

GABAergic fast-spiking parvalbumin-positive (PV) interneurons are frequently myelinated in the cerebral cortex. However, the factors governing the topography of cortical interneuron myelination remain incompletely understood. Here, we report that segmental myelination along neocortical interneuron axons is strongly predicted by the joint combination of interbranch distance and local axon caliber. Enlargement of PV+ interneurons increased axonal myelination, while reduced cell size led to decreased myelination. Next, we considered regular-spiking SOM+ cells, which normally have relatively shorter interbranch distances and thinner axon diameters than PV+ cells, and are rarely myelinated. Consistent with the importance of axonal morphology for guiding interneuron myelination, enlargement of SOM+ cell size dramatically increased the frequency of myelinated axonal segments. Lastly, we confirm that these findings also extend to human neocortex by quantifying interneuron axonal myelination from ex vivo surgical tissue. Together, these findings establish a predictive model of neocortical GABAergic interneuron myelination determined by local axonal morphology.


Assuntos
Axônios/metabolismo , Interneurônios/metabolismo , Bainha de Mielina/metabolismo , Neocórtex/metabolismo , Parvalbuminas/metabolismo , Potenciais de Ação/fisiologia , Idoso de 80 Anos ou mais , Animais , Axônios/fisiologia , Feminino , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/fisiologia , Humanos , Interneurônios/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Neocórtex/citologia , Parvalbuminas/genética , Técnicas de Patch-Clamp
18.
Hum Mutat ; 40(11): 2131-2145, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31322790

RESUMO

Noncoding RNAs have been widely recognized as essential mediators of gene regulation. However, in contrast to protein-coding genes, much less is known about the influence of noncoding RNAs on human diseases. Here we examined the association of genetic variants located in primary microRNA sequences and long noncoding RNAs (lncRNAs) with Alzheimer disease (AD) by leveraging data from the largest genome-wide association meta-analysis of late-onset AD. Variants annotated to 5 miRNAs and 10 lncRNAs (in seven distinct loci) exceeded the Bonferroni-corrected significance threshold (p < 1.02 × 10-6 ). Among these, a leading variant (rs2526377:A>G) at the 17q22 locus annotated to two noncoding RNAs (MIR142 and BZRAP1-AS) was significantly associated with a reduced risk of AD and fulfilled predefined criteria for being a functional variant. Our functional genomic analyses revealed that rs2526377 affects the promoter activity and decreases the expression of miR-142. Moreover, differential expression analysis by RNA-Seq in human iPSC-derived neural progenitor cells and the hippocampus of miR-142 knockout mice demonstrated multiple target genes of miR-142 in the brain that are likely to be involved in the inflammatory and neurodegenerative manifestations of AD. These include TGFBR1 and PICALM, of which their derepression in the brain due to reduced expression levels of miR-142-3p may reduce the risk of AD.


Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença , Variação Genética , MicroRNAs/genética , Regiões Promotoras Genéticas , Alelos , Doença de Alzheimer/metabolismo , Animais , Linhagem Celular , Mapeamento Cromossômico , Biologia Computacional/métodos , Modelos Animais de Doenças , Regulação da Expressão Gênica , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Hipocampo/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Camundongos Knockout , Modelos Biológicos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Polimorfismo de Nucleotídeo Único , Interferência de RNA , RNA não Traduzido
19.
Nat Neurosci ; 22(8): 1235-1247, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31235931

RESUMO

Mutations affecting the gene encoding the ubiquitin ligase UBE3A cause Angelman syndrome. Although most studies focus on the synaptic function of UBE3A, we show that UBE3A is highly enriched in the nucleus of mouse and human neurons. We found that the two major isoforms of UBE3A exhibit highly distinct nuclear versus cytoplasmic subcellular localization. Both isoforms undergo nuclear import through direct binding to PSMD4 (also known as S5A or RPN10), but the amino terminus of the cytoplasmic isoform prevents nuclear retention. Mice lacking the nuclear UBE3A isoform recapitulate the behavioral and electrophysiological phenotypes of Ube3am-/p+ mice, whereas mice harboring a targeted deletion of the cytosolic isoform are unaffected. Finally, we identified Angelman syndrome-associated UBE3A missense mutations that interfere with either nuclear targeting or nuclear retention of UBE3A. Taken together, our findings elucidate the mechanisms underlying the subcellular localization of UBE3A, and indicate that the nuclear UBE3A isoform is the most critical for the pathophysiology of Angelman syndrome.


Assuntos
Síndrome de Angelman/genética , Síndrome de Angelman/psicologia , Comportamento Animal , Ubiquitina-Proteína Ligases/genética , Animais , Proteínas de Transporte/metabolismo , Núcleo Celular/enzimologia , Núcleo Celular/genética , Citosol/enzimologia , Fenômenos Eletrofisiológicos/genética , Feminino , Humanos , Isoenzimas/genética , Masculino , Camundongos , Camundongos Knockout , Mutação de Sentido Incorreto/genética , Comportamento de Nidação , Neurônios/enzimologia , Desempenho Psicomotor , Proteínas de Ligação a RNA , Natação/psicologia , Dedos de Zinco
20.
Nat Commun ; 10(1): 2232, 2019 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-31110186

RESUMO

Sparse populations of neurons in the dentate gyrus (DG) of the hippocampus are causally implicated in the encoding of contextual fear memories. However, engram-specific molecular mechanisms underlying memory consolidation remain largely unknown. Here we perform unbiased RNA sequencing of DG engram neurons 24 h after contextual fear conditioning to identify transcriptome changes specific to memory consolidation. DG engram neurons exhibit a highly distinct pattern of gene expression, in which CREB-dependent transcription features prominently (P = 6.2 × 10-13), including Atf3 (P = 2.4 × 10-41), Penk (P = 1.3 × 10-15), and Kcnq3 (P = 3.1 × 10-12). Moreover, we validate the functional relevance of the RNAseq findings by establishing the causal requirement of intact CREB function specifically within the DG engram during memory consolidation, and identify a novel group of CREB target genes involved in the encoding of long-term memory.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas do Citoesqueleto/metabolismo , Giro Denteado/fisiologia , Consolidação da Memória/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Fator 3 Ativador da Transcrição/genética , Fator 3 Ativador da Transcrição/metabolismo , Animais , Condicionamento Psicológico/fisiologia , Giro Denteado/citologia , Encefalinas/genética , Encefalinas/metabolismo , Medo/fisiologia , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/fisiologia , Canal de Potássio KCNQ3/genética , Canal de Potássio KCNQ3/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Animais , Neurônios/metabolismo , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Análise de Sequência de RNA , Técnicas Estereotáxicas
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