Translational Psychiatry volume 8, Article number: 89 (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.
In summary, we found significant associations of THC- related pathways to autism and intellectual disability. Furthermore, we have used a dynamic, human-relevant system to demonstrate a phenotypic link between THC treatment and schizophrenia. We hypothesize that THC exposure, by impacting many of the same synaptic and epigenetic pathways already associated with psychiatric disorders, may serve as an additive risk to existing genetic/ epigenetic risk factors.