PT  - JOURNAL ARTICLE
AU  - Carole Shum
AU  - Lucia Dutan
AU  - Emily Annuario
AU  - Katherine Warre-Cornish
AU  - Samuel E. Taylor
AU  - Ruth D. Taylor
AU  - Laura C. Andreae
AU  - Noel J. Buckley
AU  - Jack Price
AU  - Sagnik Bhattacharyya
AU  - Deepak P. Srivastava
TI  - ∆<sup>9</sup>-tetrahydrocannabinol negatively regulates neurite outgrowth and Akt signaling in hiPSC-derived cortical neurons
AID  - 10.1101/440909
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 440909
4099  - http://biorxiv.org/content/early/2018/12/20/440909.short
4100  - http://biorxiv.org/content/early/2018/12/20/440909.full
AB  - Endocannabinoids regulate different aspects of neurodevelopment. In utero exposure to the exogenous psychoactive cannabinoid Δ9-tetrahydrocannabinol (Δ9-THC), has been linked with abnormal cortical development in animal models. However, much less is known about the actions of endocannabinoids in human neurons. Here we investigated the effect of the endogenous endocannabinoid 2-arachidonoyl glycerol (2AG) and Δ9-THC on the development of neuronal morphology and activation of signaling kinases, in cortical glutamatergic neurons derived from human induced pluripotent stem cells (hiPSCs). Our data indicate that the cannabinoid type 1 receptor (CB1R), but not the cannabinoid 2 receptor (CB2R), GPR55 or TRPV1 receptors, is expressed in young, immature hiPSC-derived cortical neurons. Consistent with previous reports, 2AG and Δ9-THC negatively regulated neurite outgrowth. Interestingly, acute exposure to both 2AG and Δ9-THC inhibited phosphorylation of serine/threonine kinase extracellular signal-regulated protein kinases (ERK1/2), whereas Δ9-THC also reduced phosphorylation of Akt (aka PKB). Moreover, the CB1R inverse agonist SR 141716A attenuated the negative regulation of neurite outgrowth and ERK1/2 phosphorylation induced by 2AG and Δ9-THC. Taken together, our data suggest that hiPSC-derived cortical neurons express CB1Rs and are responsive to both endogenous and exogenous cannabinoids. Thus, hiPSC-neurons may represent a good cellular model for investigating the role of the endocannabinoid system in regulating cellular processes in human neurons.