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1.
Transl Psychiatry ; 8(1): 89, 2018 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-29691375

RESUMO

There is a strong association between cannabis use and schizophrenia but the underlying cellular links are poorly understood. Neurons derived from human-induced pluripotent stem cells (hiPSCs) offer a platform for investigating both baseline and dynamic changes in human neural cells. Here, we exposed neurons derived from hiPSCs to Δ9-tetrahydrocannabinol (THC), and identified diagnosis-specific differences not detectable in vehicle-controls. RNA transcriptomic analyses revealed that THC administration, either by acute or chronic exposure, dampened the neuronal transcriptional response following potassium chloride (KCl)-induced neuronal depolarization. THC-treated neurons displayed significant synaptic, mitochondrial, and glutamate signaling alterations that may underlie their failure to activate appropriately; this blunted response resembles effects previously observed in schizophrenia hiPSC- derived neurons. Furthermore, we show a significant alteration in THC-related genes associated with autism and intellectual disability, suggesting shared molecular pathways perturbed in neuropsychiatric disorders that are exacerbated by THC.


Assuntos
Dronabinol/farmacologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Transtornos Mentais/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Transtorno Autístico/genética , Sequência de Bases , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ácido Glutâmico/metabolismo , Humanos , Deficiência Intelectual/genética , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Densidade Pós-Sináptica/metabolismo , Esquizofrenia/genética , Transcriptoma
2.
Mol Neuropsychiatry ; 3(2): 73-84, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29230395

RESUMO

Given the cognitive and behavioral effects following in utero Δ9-tetrahydrocannabinol (THC) exposure that have been reported in humans and rodents, it is critical to understand the precise consequences of THC on developing human neurons. Here, we utilize excitatory neurons derived from human-induced pluripotent stem cells (hiPSCs), and report that in vitro THC exposure reduced expression of glutamate receptor subunit genes (GRIA1, GRIA2, GRIN2A, and GRIN2B). By expanding these studies across hiPSC-derived neurons from individuals with a variety of genotypes, we believe that a hiPSC-based model will facilitate studies of the interaction of THC exposure and the genetic risk factors underlying neuropsychiatric disease vulnerability.

3.
Stem Cell Reports ; 9(2): 615-628, 2017 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-28757163

RESUMO

Modulation of transcription, either synthetic activation or repression, via dCas9-fusion proteins is a relatively new methodology with the potential to facilitate high-throughput up- or downregulation studies of gene function. Genetic studies of neurodevelopmental disorders have identified a growing list of risk variants, including both common single-nucleotide variants and rare copy-number variations, many of which are associated with genes having limited functional annotations. By applying a CRISPR-mediated gene-activation/repression platform to populations of human-induced pluripotent stem cell-derived neural progenitor cells, neurons, and astrocytes, we demonstrate that it is possible to manipulate endogenous expression levels of candidate neuropsychiatric risk genes across these three cell types. Although proof-of-concept studies using catalytically inactive Cas9-fusion proteins to modulate transcription have been reported, here we present a detailed survey of the reproducibility of gRNA positional effects across a variety of neurodevelopmental disorder-relevant risk genes, donors, neural cell types, and dCas9 effectors.


Assuntos
Astrócitos/citologia , Astrócitos/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Cálcio/metabolismo , Diferenciação Celular , Células Cultivadas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Imagem Molecular , Transcriptoma
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