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1.
Adv Healthc Mater ; : e1901347, 2020 Jan 15.
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.

2.
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.

3.
Hum Mutat ; 2019 Nov 06.
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.

4.
Elife ; 82019 Nov 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.

5.
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.

6.
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 , Natação/psicologia , Dedos de Zinco
7.
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 , 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
8.
Psychoneuroendocrinology ; 106: 147-154, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30981088

RESUMO

Aggression and distrust are often challenging problems in mental health treatment. Converging evidence reveals that oxytocin increases trust in social interactions and decreases fear of social betrayal. However, oxytocin has also been associated with protective behavior and, as such, might increase defensive aggressive reactions. In this randomized double-blind, placebo-controlled study, the effects of intranasal oxytocin (32IU) on task-related aggressive responses were measured using the Point Subtraction Aggression Paradigm (PSAP). Fifty-seven healthy males were enrolled and randomized to oxytocin (N = 30) or placebo (n = 27). Salivary oxytocin, cortisol and testosterone were measured serially prior to the intervention, and then before and after the PSAP, to evaluate the effects of oxytocin administration on hormonal functioning in relation to aggression. In addition, oxytocin was measured in urine collected directly after the experimental task, reflecting the 2 h period after oxytocin or placebo administration. The proportion of aggressive responses to the PSAP was significantly lower in participants receiving oxytocin versus placebo (ß= -0.46, P = 0.01). No significant effect of oxytocin was found regarding defensive reactions. Urinary oxytocin was negatively associated with the proportion of aggressive responses to the PSAP in both the oxytocin and the placebo group (ß= -0.02, P < 0.01), suggesting that higher levels of urinary oxytocin corresponded with reduced aggressive responding. Our results indicate that oxytocin administration reduces aggressive behavior in healthy young men. Moreover, increased endogenous urinary oxytocin is associated with less aggressive responding. Taken together, these findings suggest that oxytocin signaling has a causal influence on aggressive behavior.

9.
Physiol Behav ; 204: 180-185, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30802507

RESUMO

Oxytocin enhances trust during social interactions and reduces the tendency for social betrayal. Animal studies have revealed that oxytocin is also an important factor in the establishment and regulation of aggression, for which social interaction is a critical precondition. In humans, however, the effects of oxytocin appear more nuanced and influenced by social context and personality traits. Moreover, the pro-social effects of oxytocin are not mirrored by vasopressin, despite their high chemical similarity. Rather, vasopressin has been associated with an increase of aggressive responses. Therefore, we sought to investigate the association of oxytocin and vasopressin with trust and aggressive behavior. Overnight urinary oxytocin and vasopressin levels were obtained from 62 healthy males (age range: 18-26 years) to compare with trait measures of trust and aggressive behavior. We found a significant interaction of oxytocin and trust on aggression in which low trait measures of trust, in combination with low levels of oxytocin, were associated with a history of aggressive behavior. Notably, we found no significant associations for vasopressin. Although both oxytocin and vasopressin have been shown to be important in the emergence of violent behavior, our study suggests that oxytocin may be particularly modified by affiliative behaviors. These findings provide insights into the neuropsychological influences of oxytocin, and highlights the potential for clinical translation regarding the treatment of patients who exhibit recurrent aggressive behavior.

10.
Psychoneuroendocrinology ; 101: 295-303, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30599318

RESUMO

The etiology of schizophrenia is multi-factorial with early neurodevelopmental antecedents, likely to result from a complex interaction of genetic and environmental risk. However, few studies have examined how schizophrenia polygenic risk scores (PRS) are moderated by environmental factors in shaping neurodevelopmental brain structure, prior to the onset of psychotic symptoms. Here, we examined whether hair cortisol, a quantitative metric of chronic stress, moderated the association between genetic risk for schizophrenia and pre-adolescent brain structure. This study was embedded within the Generation R Study, involving pre-adolescents of European ancestry assessed regarding schizophrenia PRS, hair cortisol, and brain imaging (n = 498 structural; n = 526 diffusion tensor imaging). Linear regression was performed to determine the association between schizophrenia PRS, hair cortisol level, and brain imaging outcomes. Although no single measure exceeded the multiple testing threshold, nominally significant interactions were observed for total ventricle volume (Pinteraction = 0.02) and global white matter microstructure (Pinteraction = 0.01) - two of the most well replicated brain structural findings in schizophrenia. These findings provide suggestive evidence for the joint effects of schizophrenia liability and cortisol levels on brain correlates in the pediatric general population. Given the widely replicated finding of ventricular enlargement and lower white matter integrity among schizophrenia patients, our findings generate novel hypotheses for future research on gene-environment interactions affecting the neurodevelopmental pathophysiology of schizophrenia.

11.
Mol Psychiatry ; 24(5): 757-771, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-29302076

RESUMO

Schizophrenia is highly heritable, yet its underlying pathophysiology remains largely unknown. Among the most well-replicated findings in neurobiological studies of schizophrenia are deficits in myelination and white matter integrity; however, direct etiological genetic and cellular evidence has thus far been lacking. Here, we implement a family-based approach for genetic discovery in schizophrenia combined with functional analysis using induced pluripotent stem cells (iPSCs). We observed familial segregation of two rare missense mutations in Chondroitin Sulfate Proteoglycan 4 (CSPG4) (c.391G > A [p.A131T], MAF 7.79 × 10-5 and c.2702T > G [p.V901G], MAF 2.51 × 10-3). The CSPG4A131T mutation was absent from the Swedish Schizophrenia Exome Sequencing Study (2536 cases, 2543 controls), while the CSPG4V901G mutation was nominally enriched in cases (11 cases vs. 3 controls, P = 0.026, OR 3.77, 95% CI 1.05-13.52). CSPG4/NG2 is a hallmark protein of oligodendrocyte progenitor cells (OPCs). iPSC-derived OPCs from CSPG4A131T mutation carriers exhibited abnormal post-translational processing (P = 0.029), subcellular localization of mutant NG2 (P = 0.007), as well as aberrant cellular morphology (P = 3.0 × 10-8), viability (P = 8.9 × 10-7), and myelination potential (P = 0.038). Moreover, transfection of healthy non-carrier sibling OPCs confirmed a pathogenic effect on cell survival of both the CSPG4A131T (P = 0.006) and CSPG4V901G (P = 3.4 × 10-4) mutations. Finally, in vivo diffusion tensor imaging of CSPG4A131T mutation carriers demonstrated a reduction of brain white matter integrity compared to unaffected sibling and matched general population controls (P = 2.2 × 10-5). Together, our findings provide a convergence of genetic and functional evidence to implicate OPC dysfunction as a candidate pathophysiological mechanism of familial schizophrenia.

12.
Biol Psychiatry ; 85(4): 336-344, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30119874

RESUMO

BACKGROUND: Studies of white matter connectivity in children with disruptive behavior have yielded inconsistent results, possibly owing to the trait's heterogeneity, which comprises diverse symptoms like physical aggression, irritability, and delinquency. This study examined associations of global and specific white matter connectivity with childhood disruptive behavior problems, while accounting for their complex multidimensionality. METHODS: In a large cross-sectional population-based study of 10-year-old preadolescents (n = 2567), we assessed four previously described empirically derived dimensions of disruptive behavior problems using the Child Behavior Checklist: physical aggression, irritability, disobedient behavior, and delinquent behavior. Global and specific white matter microstructure was assessed by diffusion tensor imaging. RESULTS: Global fractional anisotropy and mean diffusivity were not associated with broad measures of disruptive behavior, e.g., Child Behavior Checklist externalizing problems scale. Global fractional anisotropy was negatively associated with delinquent behavior (ß = -.123, pfalse discovery rate adjusted = .028) and global mean diffusivity was positively associated with delinquent behavior (ß = .205, pfalse discovery rate adjusted < 0.001), suggesting reduced white matter microstructure in preadolescents with higher levels of delinquent behavior. Lower white matter microstructure in the inferior longitudinal fasciculus, superior longitudinal fasciculus, cingulum, and uncinate underlie these associations. Global white matter microstructure was not associated with physical aggression, irritability, or disobedient behavior. CONCLUSIONS: Delinquent behavior, a severe manifestation of childhood disruptive behavior, was associated with lower white matter microstructure in tracts connecting frontal and temporal lobes. These brain regions are involved in decision making, reward processing, and emotion regulation. This study demonstrated that incorporating the multidimensional nature of childhood disruptive behavior traits shows promise in advancing the search for elucidating neurobiological correlates of disruptive behavior.


Assuntos
Agressão , Lobo Frontal/anatomia & histologia , Delinquência Juvenil/estatística & dados numéricos , Comportamento Problema , Lobo Temporal/anatomia & histologia , Substância Branca/anatomia & histologia , Anisotropia , Criança , Estudos Transversais , Imagem de Tensor de Difusão , Feminino , Humanos , Testes de Inteligência , Humor Irritável , Masculino , Vias Neurais/anatomia & histologia , Neuroimagem
13.
Curr Opin Neurobiol ; 54: 163-170, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30423499

RESUMO

Extensive work in computational modeling has highlighted the advantages for employing sparse yet distributed data representation and storage Kanerva (1998), properties that extend to neuronal networks encoding mnemonic information (memory traces or engrams). While neurons that participate in an engram are distributed across multiple brain regions, within each region, the cellular sparsity of the mnemonic representation appears to be quite fixed. Although technological advances have enabled significant progress in identifying and manipulating engrams, relatively little is known about the region-dependent microcircuit rules governing the cellular sparsity of an engram. Here we review recent studies examining the mechanisms that help shape engram architecture and examine how these processes may regulate memory function. We speculate that countervailing forces in local microcircuits contribute to the generation and maintenance of engrams and discuss emerging questions regarding how engrams are formed, stored and used.


Assuntos
Encéfalo/citologia , Aprendizagem/fisiologia , Modelos Neurológicos , Rede Nervosa/fisiologia , Neurônios/fisiologia , Animais , Encéfalo/fisiologia , Simulação por Computador , Humanos
14.
Hum Mutat ; 39(12): 2008-2024, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30184290

RESUMO

The abundantly expressed calcium/calmodulin-dependent protein kinase II (CAMK2), alpha (CAMK2A), and beta (CAMK2B) isoforms are essential for learning and memory formation. Recently, a de novo candidate mutation (p.Arg292Pro) in the gamma isoform of CAMK2 (CAMK2G) was identified in a patient with severe intellectual disability (ID), but the mechanism(s) by which this mutation causes ID is unknown. Here, we identified a second, unrelated individual, with a de novo CAMK2G p.Arg292Pro mutation, and used in vivo and in vitro assays to assess the impact of this mutation on CAMK2G and neuronal function. We found that knockdown of CAMK2G results in inappropriate precocious neuronal maturation. We further found that the CAMK2G p.Arg292Pro mutation acts as a highly pathogenic gain-of-function mutation, leading to increased phosphotransferase activity and impaired neuronal maturation as well as impaired targeting of the nuclear CAMK2G isoform. Silencing the catalytic site of the CAMK2G p.Arg292Pro protein reversed the pathogenic effect of the p.Arg292Pro mutation on neuronal maturation, without rescuing its nuclear targeting. Taken together, our results reveal an indispensable function of CAMK2G in neurodevelopment and indicate that the CAMK2G p.Arg292Pro protein acts as a pathogenic gain-of-function mutation, through constitutive activity toward cytosolic targets, rather than impaired targeting to the nucleus.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Mutação com Ganho de Função , Deficiência Intelectual/genética , Substituição de Aminoácidos , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/química , Domínio Catalítico , Células Cultivadas , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Deficiência Intelectual/metabolismo , Masculino , Camundongos
15.
Schizophr Res ; 202: 322-327, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29983267

RESUMO

Cannabis use continues to increase among pregnant women. Gestational cannabis exposure has been associated with various adverse outcomes. However, it remains unclear whether cannabis use during pregnancy increases the risk for offspring psychotic-like experiences. In this prospective cohort, we examined the relationship between parental cannabis use during pregnancy and offspring psychotic-like experiences. Comparisons were made between maternal and paternal cannabis use during pregnancy to investigate causal influences of intra-uterine cannabis exposure during foetal neurodevelopmental. This study was embedded in the Generation R birth cohort and included N = 3692 participants. Maternal cannabis exposure was determined using self-reports and cannabis metabolite levels from urine. Paternal cannabis use during pregnancy was obtained by maternal report. Maternal cannabis use increased the risk of psychotic-like experiences in the offspring (ORadjusted = 1.38, 95% CI 1.03-1.85). Estimates were comparable for maternal cannabis use exclusively before pregnancy versus continued cannabis use during pregnancy. Paternal cannabis use was similarly associated with offspring psychotic-like experiences (ORadjusted = 1.44, 95% CI 1.14-1.82). We demonstrated that both maternal and paternal cannabis use were associated with more offspring psychotic-like experiences at age ten years. This may suggest that common aetiologies, rather than solely causal intra-uterine mechanisms, underlie the association between parental cannabis use and offspring psychotic-like experiences. These common backgrounds most likely reflect genetic vulnerabilities and shared familial mechanisms, shedding a potential new light on the debated causal path from cannabis use to psychotic-like phenomena. Our findings indicate that diagnostic screening and preventative measures need to be adapted for young people at risk for severe mental illness.


Assuntos
Pai/estatística & dados numéricos , Predisposição Genética para Doença/epidemiologia , Uso da Maconha/epidemiologia , Mães/estatística & dados numéricos , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Transtornos Psicóticos/epidemiologia , Adulto , Criança , Feminino , Humanos , Masculino , Uso da Maconha/efeitos adversos , Países Baixos/epidemiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Transtornos Psicóticos/etiologia
16.
BJPsych Open ; 4(4): 180-185, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29988976

RESUMO

Background: The serotonin transporter gene-linked polymorphic region (5-HTTLPR) has previously been associated with hypothalamus-pituitary-adrenal axis function. Moreover, it has been suggested that this association is moderated by an interaction with stressful life experiences. Aims: To investigate the moderation of cortisol response to psychosocial stress by 5-HTTLPR genotype, either directly or through an interaction with early life stress. Method: A total of 151 women, 85 of which had personality psychopathology, performed the Trier Social Stress Test while cortisol responsivity was assessed. Results: The results demonstrate a main effect of genotype on cortisol responsivity. Women carrying two copies of the long version of 5-HTTLPR exhibited stronger cortisol responses to psychosocial stress than women with at least one copy of the short allele (P = 0.03). However, the proportion of the variance of stress-induced cortisol responsivity explained by 5-HTTLPR genotype was not further strengthened by including early life adversity as a moderating factor (P = 0.52). Conclusions: Our results highlight the need to clarify gender-specific biological factors influencing the serotonergic system. Furthermore, our results suggest that childhood maltreatment, specifically during the first 15 years of life, is unlikely to exert a moderating influence of large effect on the relationship between the 5-HTTLPR genotype and cortisol responsivity to psychosocial stress. Declaration of interest: None.

17.
Mol Pharmacol ; 94(3): 1092-1100, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29980658

RESUMO

Zinc homeostasis is a highly regulated process in mammalian cells that is critical for normal growth and development. Movement of zinc across cell compartments is controlled by two classes of transporters: Slc39a family members transport zinc into the cytosol from either the extracellular space or intracellular stores such as the endoplasmic reticulum (ER), whereas the SLC30A family mediates zinc efflux from the cytosol. In this study, we report that genetic ablation of SLC39A7 (ZIP7) results in decreased cytosolic zinc levels, increased ER zinc levels, impaired cell proliferation, and induction of ER stress. Confirmatory of impaired zinc transport as the causal mechanism, both the increased ER stress and impaired cell proliferation were rescued by increasing cytosolic zinc. Furthermore, using these robust cellular phenotypes, we implemented a small-molecule library screen with 2800 compounds and identified one small molecule capable of rescuing ER stress and cell proliferation in ZIP7-deficient cells in the low micromolar range.


Assuntos
Proteínas de Transporte de Cátions/metabolismo , Citosol/metabolismo , Retículo Endoplasmático/metabolismo , Zinco/metabolismo , Proteínas de Transporte de Cátions/genética , Linhagem Celular , Proliferação de Células/fisiologia , Retículo Endoplasmático/genética , Estresse do Retículo Endoplasmático/fisiologia , Humanos
18.
Eur Child Adolesc Psychiatry ; 27(9): 1209-1230, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29948232

RESUMO

Lithium and antipsychotics are often prescribed to treat bipolar disorder or psychotic disorders in women of childbearing age. Little is known about the consequences of these medications during pregnancy for the developing child. The objective of this article is to systematically review findings from preclinical and clinical studies that have examined the neurodevelopmental consequences of intrauterine exposure to lithium and antipsychotics. A systematic search was performed in Embase, Medline, Web of Science, PsychINFO, Cochrane, and Google Scholar. Clinical and experimental studies were selected if they investigated neurodevelopment of offspring exposed to lithium or antipsychotics during gestation. Quality of clinical and preclinical studies was assessed by the Newcastle-Ottawa Scale and the SYRCLE's risk of Bias tool, respectively. In total, 73 studies were selected for qualitative synthesis and three studies were selected for quantitative synthesis. Of preclinical studies, 93% found one or more adverse effects of prenatal exposure to antipsychotics or lithium on neurodevelopment or behaviour. Only three clinical cohort studies have investigated the consequences of lithium exposure, all of which reported normal development. In 66% of clinical studies regarding antipsychotic exposure, a transient delay in neurodevelopment was observed. The relative risk for neuromotor deficits after in utero exposure to antipsychotics was estimated to be 1.63 (95% CI 1.22-2.19; I2 = 0%). Preclinical studies suggest long-term adverse neurodevelopmental consequences of intrauterine exposure to either lithium or antipsychotics. However, there is a lack of high-quality clinical studies. Interpretation is difficult, since most studies have compared exposed children with their peers from the unaffected population, which did not allow correction for potential influences regarding genetic predisposition or parental psychiatric illness.


Assuntos
Antipsicóticos/efeitos adversos , Lítio/efeitos adversos , Transtornos do Neurodesenvolvimento/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal , Feminino , Humanos , Lactente , Masculino , Transtornos do Neurodesenvolvimento/epidemiologia , Gravidez
19.
J Neurosci ; 38(15): 3631-3642, 2018 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-29507147

RESUMO

Axonal myelination of neocortical pyramidal neurons is modulated dynamically by neuronal activity. Recent studies have shown that a substantial proportion of neocortical myelin content is contributed by fast-spiking, parvalbumin (PV)-positive interneurons. However, it remains unknown whether the myelination of PV+ interneurons is also modulated by intrinsic activity. Here, we used cell-type-specific Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in adult mice to activate a sparse population of medial prefrontal cortex (mPFC) PV+ interneurons. Using single-cell axonal reconstructions, we found that DREADD-stimulated PV+ interneurons exhibited a nearly two-fold increase in total length of myelination, predominantly mediated by a parallel increase of axonal arborization and number of internodes. In contrast, the distribution of axonal interbranch segment distance and myelin internode length were not altered significantly. Topographical analysis revealed that myelination of DREADD-stimulated cells extended to higher axonal branch orders while retaining a similar interbranch distance threshold for myelination. Together, our results demonstrate that chemogenetically induced neuronal activity increases the myelination of neocortical PV+ interneurons mediated at least in part by an elaboration of their axonal morphology.SIGNIFICANCE STATEMENT Myelination is the wrapping of an axon to optimize conduction velocity in an energy-efficient manner. Previous studies have shown that myelination of neocortical pyramidal neurons is experience and activity dependent. We now show that activity-dependent myelin plasticity in the adult neocortex extends to parvalbumin (PV)-expressing fast-spiking interneurons. Chemogenetic stimulation of PV interneurons in the medial prefrontal cortex (mPFC) significantly enhanced axonal myelination, which was paralleled by an increase in axonal arborization. This suggests that activity-dependent axonal plasticity may involve changes in both structural morphology and myelination. Such multicomponent plasticity reveals an unexpected repertoire of anatomical parameters available for optimizing and adapting neuronal networks in response to experience.


Assuntos
Interneurônios/metabolismo , Potenciais da Membrana , Bainha de Mielina/metabolismo , Animais , Axônios/metabolismo , Axônios/fisiologia , Interneurônios/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Parvalbuminas/genética , Parvalbuminas/metabolismo , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiologia
20.
Neurol Genet ; 4(2): e223, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29577077

RESUMO

Objective: To identify the clinical characteristics and genetic etiology of a family affected with hereditary spastic paraplegia (HSP). Methods: Clinical, genetic, and functional analyses involving genome-wide linkage coupled to whole-exome sequencing in a consanguineous family with complicated HSP. Results: A homozygous missense mutation was identified in the ACO2 gene (c.1240T>G p.Phe414Val) that segregated with HSP complicated by intellectual disability and microcephaly. Lymphoblastoid cell lines of homozygous carrier patients revealed significantly decreased activity of the mitochondrial aconitase enzyme and defective mitochondrial respiration. ACO2 encodes mitochondrial aconitase, an essential enzyme in the Krebs cycle. Recessive mutations in this gene have been previously associated with cerebellar ataxia. Conclusions: Our findings nominate ACO2 as a disease-causing gene for autosomal recessive complicated HSP and provide further support for the central role of mitochondrial defects in the pathogenesis of HSP.

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