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1.
Am J Psychiatry ; : appiajp20220723, 2023 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-37915216

RESUMO

OBJECTIVE: Schizophrenia is a brain disorder that originates during neurodevelopment and has complex genetic and environmental etiologies. Despite decades of clinical evidence of altered striatal function in affected patients, studies examining its cellular and molecular mechanisms in humans are limited. To explore neurodevelopmental alterations in the striatum associated with schizophrenia, the authors established a method for the differentiation of induced pluripotent stem cells (iPSCs) into ventral forebrain organoids (VFOs). METHODS: VFOs were generated from postmortem dural fibroblast-derived iPSCs of four individuals with schizophrenia and four neurotypical control individuals for whom postmortem caudate genotypes and transcriptomic data were profiled in the BrainSeq neurogenomics consortium. Individuals were selected such that the two groups had nonoverlapping schizophrenia polygenic risk scores (PRSs). RESULTS: Single-cell RNA sequencing analyses of VFOs revealed differences in developmental trajectory between schizophrenia and control individuals in which inhibitory neuronal cells from the patients exhibited accelerated maturation. Furthermore, upregulated genes in inhibitory neurons in schizophrenia VFOs showed a significant overlap with upregulated genes in postmortem caudate tissue of individuals with schizophrenia compared with control individuals, including the donors of the iPSC cohort. CONCLUSIONS: The findings suggest that striatal neurons derived from high-PRS individuals with schizophrenia carry abnormalities that originated during early brain development and that the VFO model can recapitulate disease-relevant cell type-specific neurodevelopmental phenotypes in a dish.

2.
Neuron ; 73(3): 466-81, 2012 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-22325200

RESUMO

Neuronal development is characterized by a period of exuberant synaptic growth that is well studied. However, the mechanisms that restrict this process are less clear. Here we demonstrate that glycosylphosphatidylinositol-anchored cell-surface receptors of the Nogo Receptor family (NgR1, NgR2, and NgR3) restrict excitatory synapse formation. Loss of any one of the NgRs results in an increase in synapse number in vitro, whereas loss of all three is necessary for abnormally elevated synaptogenesis in vivo. We show that NgR1 inhibits the formation of new synapses in the postsynaptic neuron by signaling through the coreceptor TROY and RhoA. The NgR family is downregulated by neuronal activity, a response that may limit NgR function and facilitate activity-dependent synapse development. These findings suggest that NgR1, a receptor previously shown to restrict axon growth in the adult, also functions in the dendrite as a barrier that limits excitatory synapse number during brain development.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Hipocampo/citologia , Hipocampo/crescimento & desenvolvimento , Proteínas da Mielina/metabolismo , Neurônios/fisiologia , Receptores de Superfície Celular/metabolismo , Sinapses/fisiologia , Fatores Etários , Animais , Animais Recém-Nascidos , Células Cultivadas , Dendritos/genética , Dendritos/ultraestrutura , Proteína 4 Homóloga a Disks-Large , Proteínas Ligadas por GPI/deficiência , Proteínas Ligadas por GPI/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Glutamato Descarboxilase/metabolismo , Proteínas de Fluorescência Verde/genética , Guanilato Quinases/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Proteínas da Mielina/deficiência , Neurônios/citologia , Receptor Nogo 1 , Técnicas de Cultura de Órgãos , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores de Superfície Celular/deficiência , Receptores do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais/genética , Sinapses/ultraestrutura , Transfecção/métodos , Proteína rhoA de Ligação ao GTP/metabolismo
3.
Neuron ; 73(2): 292-303, 2012 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-22284184

RESUMO

Although transcription factors that repress gene expression play critical roles in nervous system development, their mechanism of action remains to be understood. Here, we report that the Olig-related transcription factor Bhlhb5 (also known as Bhlhe22) forms a repressor complex with the PR/SET domain protein, Prdm8. We find that Bhlhb5 binds to sequence-specific DNA elements and then recruits Prdm8, which mediates the repression of target genes. This interaction is critical for repressor function since mice lacking either Bhlhb5 or Prdm8 have strikingly similar cellular and behavioral phenotypes, including axonal mistargeting by neurons of the dorsal telencephalon and abnormal itch-like behavior. We provide evidence that Cadherin-11 functions as target of the Prdm8/Bhlhb5 repressor complex that must be repressed for proper neural circuit formation to occur. These findings suggest that Prdm8 is an obligate partner of Bhlhb5, forming a repressor complex that directs neural circuit assembly in part through the precise regulation of Cadherin-11.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Rede Nervosa/metabolismo , Neurônios/metabolismo , Animais , Axônios/metabolismo , Caderinas/metabolismo , Proteínas de Ligação a DNA , Histona Metiltransferases , Camundongos , Camundongos Transgênicos , Tratos Piramidais/metabolismo
4.
Neuron ; 65(6): 886-98, 2010 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-20346763

RESUMO

Itch is the least well understood of all the somatic senses, and the neural circuits that underlie this sensation are poorly defined. Here we show that the atonal-related transcription factor Bhlhb5 is transiently expressed in the dorsal horn of the developing spinal cord and appears to play a role in the formation and regulation of pruritic (itch) circuits. Mice lacking Bhlhb5 develop self-inflicted skin lesions and show significantly enhanced scratching responses to pruritic agents. Through genetic fate-mapping and conditional ablation, we provide evidence that the pruritic phenotype in Bhlhb5 mutants is due to selective loss of a subset of inhibitory interneurons in the dorsal horn. Our findings suggest that Bhlhb5 is required for the survival of a specific population of inhibitory interneurons that regulate pruritus, and provide evidence that the loss of inhibitory synaptic input results in abnormal itch.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Interneurônios/patologia , Células do Corno Posterior/patologia , Prurido/genética , Prurido/patologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Sobrevivência Celular/fisiologia , Técnicas de Introdução de Genes/métodos , Interneurônios/metabolismo , Camundongos , Camundongos Knockout , Camundongos Mutantes Neurológicos , Inibição Neural/fisiologia , Células do Corno Posterior/metabolismo , Prurido/fisiopatologia , Medula Espinal/metabolismo , Medula Espinal/patologia
5.
Neuron ; 60(4): 610-24, 2008 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-19038219

RESUMO

Neuronal activity-regulated gene expression has been suggested to be an important mediator of long-lasting, experience-dependent changes in the nervous system, but the activity-dependent component of gene transcription has never been selectively isolated and tested for its functional significance. Here, we demonstrate that introduction of a subtle knockin mutation into the mouse Bdnf gene that blocks the ability of the activity-regulated factor CREB to bind Bdnf promoter IV results in an animal in which the sensory experience-dependent induction of Bdnf expression is disrupted in the cortex. Neurons from these animals form fewer inhibitory synapses, have fewer spontaneous inhibitory quantal events, and exhibit reduced expression of inhibitory presynaptic markers in the cortex. These results indicate a specific requirement for activity-dependent Bdnf expression in the development of inhibition in the cortex and demonstrate that the activation of gene expression in response to experience-driven neuronal activity has important biological consequences in the nervous system.


Assuntos
Potenciais de Ação/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Córtex Cerebral/embriologia , Córtex Cerebral/metabolismo , Inibição Neural/genética , Neurônios/metabolismo , Transcrição Gênica/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Córtex Cerebral/fisiopatologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Potenciais Evocados/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Técnicas de Introdução de Genes , Interneurônios/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Rede Nervosa/embriologia , Rede Nervosa/metabolismo , Rede Nervosa/fisiopatologia , Regiões Promotoras Genéticas/genética , Transmissão Sináptica/genética , Ativação Transcricional/genética
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