title: Functional effects of cannabinoids during dopaminergic specification of human neural precursors derived from induced pluripotent stem cells.
abstract: Among adolescents cannabis is one of the most widely used illicit drugs. In adolescence brain development continues, characterized by neuronal maturation and synaptic plasticity. The endocannabinoid system plays an important role during brain development by modulating neuronal function and neurogenesis. Changes in endocannabinoid signaling by Δ9-tetrahydrocannabinol (THC), the psychoactive component of cannabis, might therefore lead to neurobiological changes influencing brain function and behavior. We investigated the functional maturation and dopaminergic specification of human cord blood-derived induced pluripotent stem cell (hCBiPSC)-derived small molecule neural precursor cells (smNPCs) after cultivation with the endogenous cannabinoid anandamide (AEA) and the exogenous THC, both potent agonists at the cannabinoid 1 receptor (CB1R). Higher dosages of 10-μM AEA or THC significantly decreased functionality of neurons, indicated by reduced ion currents and synaptic activity. A lower concentration of 1-μM THC had no marked effect on neuronal and dopaminergic maturation, while 1-μM AEA significantly enhanced the frequency of synaptic activity. As there were no significant effects on DNA methylation in promotor regions of genes important for neuronal function, these cannabinoid actions seem to be mediated by another than this epigenetic mechanism. Our data suggest that there are concentration-dependent actions of cannabinoids on neuronal function in vitro indicating neurotoxic, dysfunctional effects of 10-μM AEA and THC during human neurogenesis.
authors.affiliation: Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: Nancy
authors.initials: N
authors.lastname: Stanslowsky
authors.affiliation: Center for Addiction Research, Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Jahn
authors.affiliation: Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Venneri
authors.affiliation: Department of Neurology, Hannover Medical School, Hannover, Germany.|Center for Systems Neuroscience, Hannover, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Naujock
authors.affiliation: Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Haase
authors.affiliation: Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.|REBIRTH-Cluster of Excellence, Hannover, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Martin
authors.affiliation: Center for Addiction Research, Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany.|Center for Systems Neuroscience, Hannover, Germany.
authors.forename: Helge
authors.initials: H
authors.lastname: Frieling
authors.affiliation: Department of Neurology, Hannover Medical School, Hannover, Germany.|Center for Systems Neuroscience, Hannover, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Wegner
mesh_terms: D001095:Arachidonic Acids / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D019175:DNA Methylation / Q000187:drug effects; D059290:Dopaminergic Neurons / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology*; D063388:Endocannabinoids / Q000494:pharmacology*; D005312:Fetal Blood / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects*; D058953:Neural Stem Cells / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*
chemical_list: D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D013759:Dronabinol; C078814:anandamide
keywords: cannabinoids; dopaminergic differentiation; epigenetic; human induced pluripotent stem cells (hiPSCs); neurogenesis; patch clamp