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1.
Cell ; 187(8): 1853-1873.e15, 2024 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-38574728

RESUMEN

This study has followed a birth cohort for over 20 years to find factors associated with neurodevelopmental disorder (ND) diagnosis. Detailed, early-life longitudinal questionnaires captured infection and antibiotic events, stress, prenatal factors, family history, and more. Biomarkers including cord serum metabolome and lipidome, human leukocyte antigen (HLA) genotype, infant microbiota, and stool metabolome were assessed. Among the 16,440 Swedish children followed across time, 1,197 developed an ND. Significant associations emerged for future ND diagnosis in general and for specific ND subtypes, spanning intellectual disability, speech disorder, attention-deficit/hyperactivity disorder, and autism. This investigation revealed microbiome connections to future diagnosis as well as early emerging mood and gastrointestinal problems. The findings suggest links to immunodysregulation and metabolism, compounded by stress, early-life infection, and antibiotics. The convergence of infant biomarkers and risk factors in this prospective, longitudinal study on a large-scale population establishes a foundation for early-life prediction and intervention in neurodevelopment.


Asunto(s)
Biomarcadores , Microbioma Gastrointestinal , Trastornos del Neurodesarrollo , Niño , Femenino , Humanos , Lactante , Embarazo , Trastorno del Espectro Autista/microbiología , Estudios Longitudinales , Estudios Prospectivos , Heces/microbiología , Trastornos del Humor/microbiología
2.
Cell ; 178(4): 850-866.e26, 2019 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-31398340

RESUMEN

We performed a comprehensive assessment of rare inherited variation in autism spectrum disorder (ASD) by analyzing whole-genome sequences of 2,308 individuals from families with multiple affected children. We implicate 69 genes in ASD risk, including 24 passing genome-wide Bonferroni correction and 16 new ASD risk genes, most supported by rare inherited variants, a substantial extension of previous findings. Biological pathways enriched for genes harboring inherited variants represent cytoskeletal organization and ion transport, which are distinct from pathways implicated in previous studies. Nevertheless, the de novo and inherited genes contribute to a common protein-protein interaction network. We also identified structural variants (SVs) affecting non-coding regions, implicating recurrent deletions in the promoters of DLG2 and NR3C2. Loss of nr3c2 function in zebrafish disrupts sleep and social function, overlapping with human ASD-related phenotypes. These data support the utility of studying multiplex families in ASD and are available through the Hartwell Autism Research and Technology portal.


Asunto(s)
Trastorno del Espectro Autista/genética , Predisposición Genética a la Enfermedad/genética , Linaje , Mapas de Interacción de Proteínas/genética , Animales , Niño , Bases de Datos Genéticas , Modelos Animales de Enfermedad , Femenino , Eliminación de Gen , Guanilato-Quinasas/genética , Humanos , Patrón de Herencia/genética , Aprendizaje Automático , Masculino , Núcleo Familiar , Regiones Promotoras Genéticas/genética , Receptores de Mineralocorticoides/genética , Factores de Riesgo , Proteínas Supresoras de Tumor/genética , Secuenciación Completa del Genoma , Pez Cebra/genética
3.
Cell ; 178(4): 867-886.e24, 2019 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-31398341

RESUMEN

Somatosensory over-reactivity is common among patients with autism spectrum disorders (ASDs) and is hypothesized to contribute to core ASD behaviors. However, effective treatments for sensory over-reactivity and ASDs are lacking. We found distinct somatosensory neuron pathophysiological mechanisms underlie tactile abnormalities in different ASD mouse models and contribute to some ASD-related behaviors. Developmental loss of ASD-associated genes Shank3 or Mecp2 in peripheral mechanosensory neurons leads to region-specific brain abnormalities, revealing links between developmental somatosensory over-reactivity and the genesis of aberrant behaviors. Moreover, acute treatment with a peripherally restricted GABAA receptor agonist that acts directly on mechanosensory neurons reduced tactile over-reactivity in six distinct ASD models. Chronic treatment of Mecp2 and Shank3 mutant mice improved body condition, some brain abnormalities, anxiety-like behaviors, and some social impairments but not memory impairments, motor deficits, or overgrooming. Our findings reveal a potential therapeutic strategy targeting peripheral mechanosensory neurons to treat tactile over-reactivity and select ASD-related behaviors.


Asunto(s)
Trastorno del Espectro Autista/metabolismo , Agonistas del GABA/farmacología , Ácidos Isonicotínicos/farmacología , Fenotipo , Células Receptoras Sensoriales/efectos de los fármacos , Tacto/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Ansiedad/tratamiento farmacológico , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/genética , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Agonistas del GABA/uso terapéutico , Ácidos Isonicotínicos/uso terapéutico , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Proteína 2 de Unión a Metil-CpG/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Microfilamentos , Proteínas del Tejido Nervioso/genética , Inhibición Prepulso/efectos de los fármacos , Células Receptoras Sensoriales/metabolismo
4.
Cell ; 167(2): 341-354.e12, 2016 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-27667684

RESUMEN

Comparative analyses have identified genomic regions potentially involved in human evolution but do not directly assess function. Human accelerated regions (HARs) represent conserved genomic loci with elevated divergence in humans. If some HARs regulate human-specific social and behavioral traits, then mutations would likely impact cognitive and social disorders. Strikingly, rare biallelic point mutations-identified by whole-genome and targeted "HAR-ome" sequencing-showed a significant excess in individuals with ASD whose parents share common ancestry compared to familial controls, suggesting a contribution in 5% of consanguineous ASD cases. Using chromatin interaction sequencing, massively parallel reporter assays (MPRA), and transgenic mice, we identified disease-linked, biallelic HAR mutations in active enhancers for CUX1, PTBP2, GPC4, CDKL5, and other genes implicated in neural function, ASD, or both. Our data provide genetic evidence that specific HARs are essential for normal development, consistent with suggestions that their evolutionary changes may have altered social and/or cognitive behavior. PAPERCLIP.


Asunto(s)
Trastorno del Espectro Autista/genética , Cognición , Predisposición Genética a la Enfermedad , Neurogénesis/genética , Mutación Puntual , Conducta Social , Alelos , Animales , Corteza Cerebral/metabolismo , Dosificación de Gen , Variación Genética , Genoma Humano , Proteínas de Homeodominio/genética , Humanos , Intrones , Ratones , Ratones Transgénicos , Proteínas Nucleares/genética , Sitios de Carácter Cuantitativo , Elementos Reguladores de la Transcripción , Proteínas Represoras/genética , Factores de Transcripción
5.
Cell ; 167(6): 1481-1494.e18, 2016 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-27912058

RESUMEN

Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched-chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here, we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation, and severe neurological abnormalities. Furthermore, we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. Finally, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA in human brain function.


Asunto(s)
Trastorno del Espectro Autista/genética , Barrera Hematoencefálica/fisiopatología , Transportador de Aminoácidos Neutros Grandes 1/metabolismo , Mutación , Aminoácidos/administración & dosificación , Aminoácidos/metabolismo , Animales , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/patología , Trastorno del Espectro Autista/fisiopatología , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/fisiopatología , Femenino , Humanos , Lactante , Recién Nacido , Transportador de Aminoácidos Neutros Grandes 1/genética , Masculino , Ratones , Ratones Noqueados , Linaje , Biosíntesis de Proteínas , Receptor TIE-2/genética
6.
Am J Hum Genet ; 2024 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-39419027

RESUMEN

Microtubule affinity-regulating kinase 2 (MARK2) contributes to establishing neuronal polarity and developing dendritic spines. Although large-scale sequencing studies have associated MARK2 variants with autism spectrum disorder (ASD), the clinical features and variant spectrum in affected individuals with MARK2 variants, early developmental phenotypes in mutant human neurons, and the pathogenic mechanism underlying effects on neuronal development have remained unclear. Here, we report 31 individuals with MARK2 variants and presenting with ASD, other neurodevelopmental disorders, and distinctive facial features. Loss-of-function (LoF) variants predominate (81%) in affected individuals, while computational analysis and in vitro expression assay of missense variants supported the effect of MARK2 loss. Using proband-derived and CRISPR-engineered isogenic induced pluripotent stem cells (iPSCs), we show that MARK2 loss leads to early neuronal developmental and functional deficits, including anomalous polarity and dis-organization in neural rosettes, as well as imbalanced proliferation and differentiation in neural progenitor cells (NPCs). Mark2+/- mice showed abnormal cortical formation and partition and ASD-like behavior. Through the use of RNA sequencing (RNA-seq) and lithium treatment, we link MARK2 loss to downregulation of the WNT/ß-catenin signaling pathway and identify lithium as a potential drug for treating MARK2-associated ASD.

7.
Am J Hum Genet ; 110(10): 1750-1768, 2023 10 05.
Artículo en Inglés | MEDLINE | ID: mdl-37802044

RESUMEN

Whole-exome sequencing of autism spectrum disorder (ASD) probands and unaffected family members has identified many genes harboring de novo variants suspected to play a causal role in the disorder. Of these, chromodomain helicase DNA-binding protein 8 (CHD8) is the most recurrently mutated. Despite the prevalence of CHD8 mutations, we have little insight into how CHD8 loss affects genome organization or the functional consequences of these molecular alterations in neurons. Here, we engineered two isogenic human embryonic stem cell lines with CHD8 loss-of-function mutations and characterized differences in differentiated human cortical neurons. We identified hundreds of genes with altered expression, including many involved in neural development and excitatory synaptic transmission. Field recordings and single-cell electrophysiology revealed a 3-fold decrease in firing rates and synaptic activity in CHD8+/- neurons, as well as a similar firing-rate deficit in primary cortical neurons from Chd8+/- mice. These alterations in neuron and synapse function can be reversed by CHD8 overexpression. Moreover, CHD8+/- neurons displayed a large increase in open chromatin across the genome, where the greatest change in compaction was near autism susceptibility candidate 2 (AUTS2), which encodes a transcriptional regulator implicated in ASD. Genes with changes in chromatin accessibility and expression in CHD8+/- neurons have significant overlap with genes mutated in probands for ASD, intellectual disability, and schizophrenia but not with genes mutated in healthy controls or other disease cohorts. Overall, this study characterizes key molecular alterations in genome structure and expression in CHD8+/- neurons and links these changes to impaired neuronal and synaptic function.


Asunto(s)
Trastorno del Espectro Autista , Trastorno Autístico , Humanos , Animales , Ratones , Trastorno Autístico/genética , Trastorno del Espectro Autista/genética , Cromatina/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Expresión Génica , Factores de Transcripción/genética
8.
Am J Hum Genet ; 110(5): 826-845, 2023 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-37098352

RESUMEN

Alterations in cortical neurogenesis are implicated in neurodevelopmental disorders including autism spectrum disorders (ASDs). The contribution of genetic backgrounds, in addition to ASD risk genes, on cortical neurogenesis remains understudied. Here, using isogenic induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) and cortical organoid models, we report that a heterozygous PTEN c.403A>C (p.Ile135Leu) variant found in an ASD-affected individual with macrocephaly dysregulates cortical neurogenesis in an ASD-genetic-background-dependent fashion. Transcriptome analysis at both bulk and single-cell level revealed that the PTEN c.403A>C variant and ASD genetic background affected genes involved in neurogenesis, neural development, and synapse signaling. We also found that this PTEN p.Ile135Leu variant led to overproduction of NPC subtypes as well as neuronal subtypes including both deep and upper layer neurons in its ASD background, but not when introduced into a control genetic background. These findings provide experimental evidence that both the PTEN p.Ile135Leu variant and ASD genetic background contribute to cellular features consistent with ASD associated with macrocephaly.


Asunto(s)
Trastorno del Espectro Autista , Trastorno Autístico , Células Madre Pluripotentes Inducidas , Megalencefalia , Células-Madre Neurales , Humanos , Trastorno del Espectro Autista/genética , Trastorno Autístico/genética , Megalencefalia/genética , Neurogénesis/genética , Neuronas , Fosfohidrolasa PTEN/genética
9.
Development ; 150(4)2023 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-36826401

RESUMEN

Inhibitory interneurons regulate cortical circuit activity, and their dysfunction has been implicated in autism spectrum disorder (ASD). 16p11.2 microdeletions are genetically linked to 1% of ASD cases. However, few studies investigate the effects of this microdeletion on interneuron development. Using ventral telencephalic organoids derived from human induced pluripotent stem cells, we have investigated the effect of this microdeletion on organoid size, progenitor proliferation and organisation into neural rosettes, ganglionic eminence marker expression at early developmental timepoints, and expression of the neuronal marker NEUN at later stages. At early stages, deletion organoids exhibited greater variations in size with concomitant increases in relative neural rosette area and the expression of the ventral telencephalic marker COUPTFII, with increased variability in these properties. Cell cycle analysis revealed an increase in total cell cycle length caused primarily by an elongated G1 phase, the duration of which also varied more than normal. At later stages, deletion organoids increased their NEUN expression. We propose that 16p11.2 microdeletions increase developmental variability and may contribute to ASD aetiology by lengthening the cell cycle of ventral progenitors, promoting premature differentiation into interneurons.


Asunto(s)
Trastorno del Espectro Autista , Células Madre Pluripotentes Inducidas , Humanos , Trastorno del Espectro Autista/metabolismo , Telencéfalo , Neuronas/metabolismo , Interneuronas/metabolismo , Organoides
10.
EMBO Rep ; 25(3): 1282-1309, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38316900

RESUMEN

UBE3A is a common genetic factor in ASD etiology, and transgenic mice overexpressing UBE3A exhibit typical autistic-like behaviors. Because AMPA receptors (AMPARs) mediate most of the excitatory synaptic transmission in the brain, and synaptic dysregulation is considered one of the primary cellular mechanisms in ASD pathology, we investigate here the involvement of AMPARs in UBE3A-dependent ASD. We show that expression of the AMPAR GluA1 subunit is decreased in UBE3A-overexpressing mice, and that AMPAR-mediated neuronal activity is reduced. GluA1 mRNA is trapped in the nucleus of UBE3A-overexpressing neurons, suppressing GluA1 protein synthesis. Also, SARNP, an mRNA nuclear export protein, is downregulated in UBE3A-overexpressing neurons, causing GluA1 mRNA nuclear retention. Restoring SARNP levels not only rescues GluA1 mRNA localization and protein expression, but also normalizes neuronal activity and autistic behaviors in mice overexpressing UBE3A. These findings indicate that SARNP plays a crucial role in the cellular and behavioral phenotypes of UBE3A-induced ASD by regulating nuclear mRNA trafficking and protein translation of a key AMPAR subunit.


Asunto(s)
Trastorno Autístico , Animales , Ratones , Ratones Transgénicos , Neuronas/metabolismo , Procesamiento Proteico-Postraduccional , Transmisión Sináptica/fisiología
11.
Proc Natl Acad Sci U S A ; 120(10): e2206758120, 2023 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-36862688

RESUMEN

Autism spectrum disorder (ASD) is a highly heterogeneous disorder, yet transcriptomic profiling of bulk brain tissue has identified substantial convergence among dysregulated genes and pathways in ASD. However, this approach lacks cell-specific resolution. We performed comprehensive transcriptomic analyses on bulk tissue and laser-capture microdissected (LCM) neurons from 59 postmortem human brains (27 ASD and 32 controls) in the superior temporal gyrus (STG) of individuals ranging from 2 to 73 years of age. In bulk tissue, synaptic signaling, heat shock protein-related pathways, and RNA splicing were significantly altered in ASD. There was age-dependent dysregulation of genes involved in gamma aminobutyric acid (GABA) (GAD1 and GAD2) and glutamate (SLC38A1) signaling pathways. In LCM neurons, AP-1-mediated neuroinflammation and insulin/IGF-1 signaling pathways were upregulated in ASD, while mitochondrial function, ribosome, and spliceosome components were downregulated. GABA synthesizing enzymes GAD1 and GAD2 were both downregulated in ASD neurons. Mechanistic modeling suggested a direct link between inflammation and ASD in neurons, and prioritized inflammation-associated genes for future study. Alterations in small nucleolar RNAs (snoRNAs) associated with splicing events suggested interplay between snoRNA dysregulation and splicing disruption in neurons of individuals with ASD. Our findings supported the fundamental hypothesis of altered neuronal communication in ASD, demonstrated that inflammation was elevated at least in part in ASD neurons, and may reveal windows of opportunity for biotherapeutics to target the trajectory of gene expression and clinical manifestation of ASD throughout the human lifespan.


Asunto(s)
Trastorno del Espectro Autista , Transcriptoma , Humanos , Enfermedades Neuroinflamatorias , Trastorno del Espectro Autista/genética , Inflamación/genética , Neuronas , Ácido Glutámico
12.
Proc Natl Acad Sci U S A ; 120(31): e2215632120, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37506195

RESUMEN

Autism spectrum disorder (ASD) has a complex genetic architecture involving contributions from both de novo and inherited variation. Few studies have been designed to address the role of rare inherited variation or its interaction with common polygenic risk in ASD. Here, we performed whole-genome sequencing of the largest cohort of multiplex families to date, consisting of 4,551 individuals in 1,004 families having two or more autistic children. Using this study design, we identify seven previously unrecognized ASD risk genes supported by a majority of rare inherited variants, finding support for a total of 74 genes in our cohort and a total of 152 genes after combined analysis with other studies. Autistic children from multiplex families demonstrate an increased burden of rare inherited protein-truncating variants in known ASD risk genes. We also find that ASD polygenic score (PGS) is overtransmitted from nonautistic parents to autistic children who also harbor rare inherited variants, consistent with combinatorial effects in the offspring, which may explain the reduced penetrance of these rare variants in parents. We also observe that in addition to social dysfunction, language delay is associated with ASD PGS overtransmission. These results are consistent with an additive complex genetic risk architecture of ASD involving rare and common variation and further suggest that language delay is a core biological feature of ASD.


Asunto(s)
Trastorno del Espectro Autista , Trastornos del Desarrollo del Lenguaje , Niño , Humanos , Trastorno del Espectro Autista/genética , Herencia Multifactorial/genética , Padres , Secuenciación Completa del Genoma , Predisposición Genética a la Enfermedad
13.
J Neurosci ; 44(39)2024 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-39164108

RESUMEN

Communication in the form of nonverbal, social vocalization, or crying is evolutionary conserved in mammals and is impaired early in human infants that are later diagnosed with autism spectrum disorder (ASD). Defects in infant vocalization have been proposed as an early sign of ASD that may exacerbate ASD development. However, the neural mechanisms associated with early communicative deficits in ASD are not known. Here, we expressed a constitutively active mutant of Rheb (RhebS16H), which is known to upregulate two ASD core pathways, mTOR complex 1 (mTORC1) and ERK1/2, in Layer (L) 2/3 pyramidal neurons of the neocortex of mice of either sex. We found that cellular mosaic expression of RhebS16H in L2/3 pyramidal neurons altered the production of isolation calls from neonatal mice. This was accompanied by an expected misplacement of neurons and dendrite overgrowth, along with an unexpected increase in spine density and length, which was associated with increased excitatory synaptic activity. This contrasted with the known decrease in spine density in RhebS16H neurons of 1-month-old mice. Reducing the levels of the actin cross-linking and adaptor protein filamin A (FLNA), known to be increased downstream of ERK1/2, attenuated dendrite overgrowth and fully restored spine properties, synaptic connectivity, and the production of pup isolation calls. These findings suggest that upper-layer cortical pyramidal neurons contribute to communicative deficits in a condition known to affect two core ASD pathways and that these mechanisms are regulated by FLNA.


Asunto(s)
Trastorno del Espectro Autista , Filaminas , Células Piramidales , Animales , Femenino , Masculino , Ratones , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Corteza Cerebral/metabolismo , Filaminas/metabolismo , Filaminas/genética , Ratones Endogámicos C57BL , Ratones Transgénicos , Mosaicismo , Células Piramidales/metabolismo , Células Piramidales/fisiología , Sinapsis/metabolismo , Sinapsis/fisiología , Vocalización Animal/fisiología
14.
Am J Hum Genet ; 109(12): 2141-2151, 2022 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-36417915

RESUMEN

As genomic and personalized medicine becomes mainstream, assessing and understanding the public's genetic literacy is paramount. Because genetic research drives innovation and involves much of the public, it is equally important to assess its impact on genetic literacy. We designed a survey to assess genetic literacy in three ways (familiarity, knowledge, and skills) and distributed it to two distinct samples: 2,050 members of the general population and 2,023 individuals currently enrolled in a large-scale genetic research study. We compared these data to a similar survey implemented in 2013. The results indicate that familiarity with basic genetic terms in 2021 (M = 5.36 [range 1-7], p < 0.001) and knowledge of genetic concepts in 2021 (M = 9.06 [56.6% correct], p = 0.002) are significantly higher compared to 2013 (familiarity: M = 5.08 [range 1-7]; knowledge: M = 8.72 [54.5% correct]). Those currently enrolled in a genetic study were also significantly more familiar with genetic terms (M = 5.79 [range 1-7], p < 0.001) and more knowledgeable of genetic concepts (M = 10.57 [66.1% correct], p < 0.001), and they scored higher in skills (M = 3.57 [59.5% correct], p < 0.001) than the general population (M = 5.36 [range 1-7]; M = 9.06 [56.6% correct]; M = 2.65 [44.2% correct]). The results suggest that genetic literacy is improving over time, with room for improvement. We conclude that educational interventions are needed to ensure familiarity with and comprehension of basic genetic concepts and suggest further exploration of the impact of genetic research participation on genetic literacy to determine mechanisms for potential interventions.


Asunto(s)
Investigación Genética , Alfabetización , Humanos , Genómica , Medicina de Precisión
15.
Am J Hum Genet ; 109(8): 1436-1457, 2022 08 04.
Artículo en Inglés | MEDLINE | ID: mdl-35907405

RESUMEN

ADGRL1 (latrophilin 1), a well-characterized adhesion G protein-coupled receptor, has been implicated in synaptic development, maturation, and activity. However, the role of ADGRL1 in human disease has been elusive. Here, we describe ten individuals with variable neurodevelopmental features including developmental delay, intellectual disability, attention deficit hyperactivity and autism spectrum disorders, and epilepsy, all heterozygous for variants in ADGRL1. In vitro, human ADGRL1 variants expressed in neuroblastoma cells showed faulty ligand-induced regulation of intracellular Ca2+ influx, consistent with haploinsufficiency. In vivo, Adgrl1 was knocked out in mice and studied on two genetic backgrounds. On a non-permissive background, mice carrying a heterozygous Adgrl1 null allele exhibited neurological and developmental abnormalities, while homozygous mice were non-viable. On a permissive background, knockout animals were also born at sub-Mendelian ratios, but many Adgrl1 null mice survived gestation and reached adulthood. Adgrl1-/- mice demonstrated stereotypic behaviors, sexual dysfunction, bimodal extremes of locomotion, augmented startle reflex, and attenuated pre-pulse inhibition, which responded to risperidone. Ex vivo synaptic preparations displayed increased spontaneous exocytosis of dopamine, acetylcholine, and glutamate, but Adgrl1-/- neurons formed synapses in vitro poorly. Overall, our findings demonstrate that ADGRL1 haploinsufficiency leads to consistent developmental, neurological, and behavioral abnormalities in mice and humans.


Asunto(s)
Trastorno del Espectro Autista , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Receptores Acoplados a Proteínas G , Receptores de Péptidos , Adulto , Animales , Trastorno del Espectro Autista/genética , Modelos Animales de Enfermedad , Haploinsuficiencia/genética , Humanos , Discapacidad Intelectual/genética , Ratones , Ratones Noqueados , Trastornos del Neurodesarrollo/genética
16.
Genes Cells ; 29(9): 746-756, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38964745

RESUMEN

An autism-associated gene Shank3 encodes multiple splicing isoforms, Shank3a-f. We have recently reported that Shank3a/b-knockout mice were more susceptible to kainic acid-induced seizures than wild-type mice at 4 weeks of age. Little is known, however, about how the N-terminal and ankyrin repeat domains (NT-Ank) of Shank3a/b regulate multiple molecular signals in the developing brain. To explore the functional roles of Shank3a/b, we performed a mass spectrometry-based proteomic search for proteins interacting with GFP-tagged NT-Ank. In this study, NT-Ank was predicted to form a variety of complexes with a total of 348 proteins, in which RNA-binding (n = 102), spliceosome (n = 22), and ribosome-associated molecules (n = 9) were significantly enriched. Among them, an X-linked intellectual disability-associated protein, Nono, was identified as a NT-Ank-binding protein. Coimmunoprecipitation assays validated the interaction of Shank3 with Nono in the mouse brain. In agreement with these data, the thalamus of Shank3a/b-knockout mice aberrantly expressed splicing isoforms of autism-associated genes, Nrxn1 and Eif4G1, before and after seizures with kainic acid treatment. These data indicate that Shank3 interacts with multiple RNA-binding proteins in the postnatal brain, thereby regulating the homeostatic expression of splicing isoforms for autism-associated genes after birth.


Asunto(s)
Ratones Noqueados , Proteínas del Tejido Nervioso , Proteínas de Unión al ARN , Animales , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Ratones , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Repetición de Anquirina , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Microfilamentos/metabolismo , Proteínas de Microfilamentos/genética , Empalme del ARN , Encéfalo/metabolismo , Convulsiones/metabolismo , Convulsiones/genética , Convulsiones/inducido químicamente , Humanos , Unión Proteica , Ratones Endogámicos C57BL
17.
Cereb Cortex ; 34(2)2024 01 31.
Artículo en Inglés | MEDLINE | ID: mdl-38282456

RESUMEN

While disruptions in brain maturation in the first years of life in ASD are well documented, little is known about how the brain structure and function are related in young children with ASD compared to typically developing peers. We applied a multivariate pattern analysis to examine the covariation patterns between brain morphometry and local brain spontaneous activity in 38 toddlers and preschoolers with ASD and 31 typically developing children using T1-weighted structural MRI and resting-state fMRI data acquired during natural sleep. The results revealed significantly reduced brain structure-function correlations in ASD. The resultant brain structure and function composite indices were associated with age among typically developing children, but not among those with ASD, suggesting mistiming of typical brain maturational trajectories early in life in autism. Additionally, the brain function composite indices were associated with the overall developmental and adaptive behavior skills in the ASD group, highlighting the neurodevelopmental significance of early local brain activity in autism.


Asunto(s)
Trastorno del Espectro Autista , Trastorno Autístico , Humanos , Preescolar , Trastorno del Espectro Autista/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Imagen por Resonancia Magnética
18.
Proc Natl Acad Sci U S A ; 119(8)2022 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-35165191

RESUMEN

FOXP1 syndrome caused by haploinsufficiency of the forkhead box protein P1 (FOXP1) gene is a neurodevelopmental disorder that manifests motor dysfunction, intellectual disability, autism, and language impairment. In this study, we used a Foxp1+/- mouse model to address whether cognitive and motor deficits in FOXP1 syndrome are associated with mitochondrial dysfunction and oxidative stress. Here, we show that genes with a role in mitochondrial biogenesis and dynamics (e.g., Foxo1, Pgc-1α, Tfam, Opa1, and Drp1) were dysregulated in the striatum of Foxp1+/- mice at different postnatal stages. Furthermore, these animals exhibit a reduced mitochondrial membrane potential and complex I activity, as well as decreased expression of the antioxidants superoxide dismutase 2 (Sod2) and glutathione (GSH), resulting in increased oxidative stress and lipid peroxidation. These features can explain the reduced neurite branching, learning and memory, endurance, and motor coordination that we observed in these animals. Taken together, we provide strong evidence of mitochondrial dysfunction in Foxp1+/- mice, suggesting that insufficient energy supply and excessive oxidative stress underlie the cognitive and motor impairment in FOXP1 deficiency.


Asunto(s)
Factores de Transcripción Forkhead/genética , Discapacidad Intelectual/genética , Trastornos Motores/genética , Proteínas Represoras/genética , Animales , Trastorno del Espectro Autista/genética , Trastorno Autístico/metabolismo , Cognición/fisiología , Modelos Animales de Enfermedad , Factores de Transcripción Forkhead/deficiencia , Factores de Transcripción Forkhead/metabolismo , Haploinsuficiencia/genética , Ratones , Ratones Endogámicos C57BL , Mitocondrias/genética , Mitocondrias/metabolismo , Actividad Motora/genética , Trastornos Motores/metabolismo , Trastornos del Neurodesarrollo/metabolismo , Neurogénesis , Estrés Oxidativo/fisiología , Proteínas Represoras/deficiencia , Proteínas Represoras/metabolismo
19.
BMC Biol ; 22(1): 142, 2024 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-38926759

RESUMEN

BACKGROUND: The VPS50 protein functions in synaptic and dense core vesicle acidification, and perturbations of VPS50 function produce behavioral changes in Caenorhabditis elegans. Patients with mutations in VPS50 show severe developmental delay and intellectual disability, characteristics that have been associated with autism spectrum disorders (ASDs). The mechanisms that link VPS50 mutations to ASD are unknown. RESULTS: To examine the role of VPS50 in mammalian brain function and behavior, we used the CRISPR/Cas9 system to generate knockouts of VPS50 in both cultured murine cortical neurons and living mice. In cultured neurons, KO of VPS50 did not affect the number of synaptic vesicles but did cause mislocalization of the V-ATPase V1 domain pump and impaired synaptic activity, likely as a consequence of defects in vesicle acidification and vesicle content. In mice, mosaic KO of VPS50 in the hippocampus altered synaptic transmission and plasticity and generated robust cognitive impairments. CONCLUSIONS: We propose that VPS50 functions as an accessory protein to aid the recruitment of the V-ATPase V1 domain to synaptic vesicles and in that way plays a crucial role in controlling synaptic vesicle acidification. Understanding the mechanisms controlling behaviors and synaptic function in ASD-associated mutations is pivotal for the development of targeted interventions, which may open new avenues for therapeutic strategies aimed at ASD and related conditions.


Asunto(s)
Ratones Noqueados , Vesículas Sinápticas , Animales , Ratones , Conducta Animal/fisiología , Encéfalo/metabolismo , Neuronas/metabolismo , Neuronas/fisiología , Sinapsis/metabolismo , Sinapsis/fisiología , Transmisión Sináptica , Vesículas Sinápticas/metabolismo , ATPasas de Translocación de Protón Vacuolares/metabolismo , ATPasas de Translocación de Protón Vacuolares/genética , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo
20.
J Neurosci ; 43(40): 6779-6795, 2023 10 04.
Artículo en Inglés | MEDLINE | ID: mdl-37607822

RESUMEN

Communication difficulties are one of the core criteria in diagnosing autism spectrum disorder (ASD), and are often characterized by speech reception difficulties, whose biological underpinnings are not yet identified. This deficit could denote atypical neuronal ensemble activity, as reflected by neural oscillations. Atypical cross-frequency oscillation coupling, in particular, could disrupt the joint tracking and prediction of dynamic acoustic stimuli, a dual process that is essential for speech comprehension. Whether such oscillatory anomalies already exist in very young children with ASD, and with what specificity they relate to individual language reception capacity is unknown. We collected neural activity data using electroencephalography (EEG) in 64 very young children with and without ASD (mean age 3; 17 females, 47 males) while they were exposed to naturalistic-continuous speech. EEG power of frequency bands typically associated with phrase-level chunking (δ, 1-3 Hz), phonemic encoding (low-γ, 25-35 Hz), and top-down control (ß, 12-20 Hz) were markedly reduced in ASD relative to typically developing (TD) children. Speech neural tracking by δ and θ (4-8 Hz) oscillations was also weaker in ASD compared with TD children. After controlling gaze-pattern differences, we found that the classical θ/γ coupling was replaced by an atypical ß/γ coupling in children with ASD. This anomaly was the single most specific predictor of individual speech reception difficulties in ASD children. These findings suggest that early interventions (e.g., neurostimulation) targeting the disruption of ß/γ coupling and the upregulation of θ/γ coupling could improve speech processing coordination in young children with ASD and help them engage in oral interactions.SIGNIFICANCE STATEMENT Very young children already present marked alterations of neural oscillatory activity in response to natural speech at the time of autism spectrum disorder (ASD) diagnosis. Hierarchical processing of phonemic-range and syllabic-range information (θ/γ coupling) is disrupted in ASD children. Abnormal bottom-up (low-γ) and top-down (low-ß) coordination specifically predicts speech reception deficits in very young ASD children, and no other cognitive deficit.


Asunto(s)
Trastorno del Espectro Autista , Trastorno Autístico , Masculino , Femenino , Humanos , Niño , Preescolar , Habla/fisiología , Trastorno del Espectro Autista/diagnóstico , Electroencefalografía , Estimulación Acústica
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