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THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders.

ABSTRACT: 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 ?9-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.

SUBMITTER: Guennewig B

PROVIDER: S-EPMC5915454 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders.

Guennewig Boris B Bitar Maina M Obiorah Ifeanyi I Hanks James J O'Brien Elizabeth A EA Kaczorowski Dominik C DC Hurd Yasmin L YL Roussos Panos P Brennand Kristen J KJ Barry Guy G

Translational psychiatry 20180425 1

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 Δ<sup>9</sup>-tetrahydrocannabinol (THC), and identified diagnosis-specific differences not detectable in vehicle-controls. RNA transcriptomic analyses revealed that T ...[more]

PMID: 29691375

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Project description:OBJECTIVE:Neurodevelopmental disorders presumably involve events that occur during brain development. The authors hypothesized that neuropsychiatric disorders considered to be developmental in etiology are associated with susceptibility genes that are relatively upregulated during fetal life (i.e., differentially expressed). METHOD:The authors investigated the presence of prenatal expression enrichment of susceptibility genes systematically, as composite gene sets associated with six neuropsychiatric disorders in the microarray-based "BrainCloud" dorsolateral prefrontal cortex transcriptome. RESULTS:Using a fetal/postnatal log2-fold change threshold of 0.5, genes associated with syndromic neurodevelopmental disorders (N=31 genes, p=3.37×10-3), intellectual disability (N=88 genes, p=5.53×10-3), and autism spectrum disorder (N=242 genes, p=3.45×10-4) were relatively enriched in prenatal transcript abundance, compared with the overall transcriptome. Genes associated with schizophrenia by genome-wide association studies were not preferentially fetally expressed (N=106 genes, p=0.46), nor were genes associated with schizophrenia by exome sequencing (N=212 genes, p=0.21), but specific genes within copy-number variant regions associated with schizophrenia were relatively enriched in prenatal transcript abundance, and genes associated with schizophrenia by meta-analysis were functionally enriched for some neurodevelopmental processes. In contrast, genes associated with neurodegenerative disorders were significantly underexpressed during fetal life (N=46 genes, p=1.67×10-3). CONCLUSIONS:The authors found evidence for relative prenatal enrichment of putative susceptibility genes for syndromic neurodevelopmental disorders, intellectual disability, and autism spectrum disorder. Future transcriptome-level association studies should evaluate regions other than the dorsolateral prefrontal cortex, at other time points, and incorporate further RNA sequencing analyses.

Project description:Delta-9-tetrahydrocannabinol (?9-THC) is a naturally occurring psychoactive compound derived from the hemp plant Cannabis sativa. In 2015, EFSA established an acute reference dose (ARfD) of 1 ?g/kg body weight (bw) for ?9-THC and assessed acute dietary exposure from milk and dairy products. This resulted at the most 3% and 13% of the ARfD for adults and toddlers, respectively. Following the European Commission Recommendation 2016/2115 on the monitoring of the presence of ?9-THC in food and the issuing of a new mandate, EFSA assessed the acute human exposure to ?9-THC. 'Standard' food categories were used as proxies for consumption of hemp and hemp-based products. Twelve independent scenarios based on single food categories were considered and acute exposure was assessed for consumption days only for all age groups excluding infants. Occurrence data for Total-?9-THC (588 samples in total) were used for this assessment up to the highest reliable percentile for each food category. The EFSA ARfD of 1 ?g/kg bw was exceeded in the adult high consumers of most considered hemp and hemp-containing products, under the lower-bound (LB) and upper-bound (UB) scenario. At the UB, acute exposure in adult high consumers was estimated based on the highest reliable percentile of occurrence, for Hemp seeds (P95, up to 9 ?g/kg bw), Hemp oil (P95, up to 21 ?g/kg bw), Tea (Infusion) (P95, up to 208 ?g/kg bw), Breakfast cereals (P50, up to 1.3 ?g/kg bw), Pasta (Raw) (P75, up to 6.4 ?g/kg bw), Bread and rolls (P75, up to 1.3 ?g/kg bw), Bread and rolls from hemp flour (P90, up to 4.1 ?g/kg bw), Cereal bars (P50, up to 0.3 ?g/kg bw), Fine bakery wares (P75, up to 5.1 ?g/kg bw), Chocolate (Cocoa) products (P75, up to 1.1 ?g/kg bw), Energy drinks (P75, up to 0.2 ?g/kg bw), Dietary supplements (P75, up to 9.9 ?g/kg bw), Beer and beer-like beverages (P90, up to 41 ?g/kg bw). The use of proxies for the consumption of hemp and hemp-containing products, the limited number of occurrence data and the analytical limitations in the quantification of ?9-THC represent the most important sources of uncertainty. Overall, exposure estimates presented in this report are expected to represent an overestimation of acute exposure to ?9-THC in the EU.

Dataset Information

THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders.

Publications

THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders.

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