THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders.
Boris GuennewigMaina BitarIfeanyi ObiorahJames HanksElizabeth A O'BrienDominik C KaczorowskiYasmin L HurdPanos RoussosKristen J BrennandGuy BarryPublished in: Translational psychiatry (2018)
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.
Keyphrases
- induced pluripotent stem cells
- intellectual disability
- endothelial cells
- spinal cord
- autism spectrum disorder
- bipolar disorder
- gene expression
- single cell
- high glucose
- drug induced
- pluripotent stem cells
- high throughput
- spinal cord injury
- transcription factor
- rna seq
- signaling pathway
- brain injury
- single molecule
- endoplasmic reticulum stress
- newly diagnosed
- stress induced