Pharmacological characterisation of ligand- and voltage-gated ion channels expressed in human iPSC-derived forebrain neurons

• Published in: Psychopharmacology Vol. 231; no. 6; pp. 1105 - 1124
• Main Authors: Dage, Jeffrey L., Colvin, Ellen M., Fouillet, Antoine, Langron, Emily, Roell, William C., Li, Jingling, Mathur, Sachin X., Mogg, Adrian J., Schmitt, Matthew G., Felder, Christian C., Merchant, Kalpana M., Isaac, John, Broad, Lisa M., Sher, Emanuele, Ursu, Daniel
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.03.2014; Springer; Springer Nature B.V
• Subjects: Analysis; Aspartate; Autism; Biomedical and Life Sciences; Biomedicine; Brain; Calcium - metabolism; Calcium Channels - metabolism; Care and treatment; Diagnosis; GABA; Gene Expression; Glutamate; Health aspects; Humans; Induced Pluripotent Stem Cells - drug effects; Induced Pluripotent Stem Cells - physiology; Ion Channels - metabolism; Membrane Potentials - drug effects; Membrane Potentials - physiology; Methyl aspartate; Nervous system diseases; Neurobiology; Neurons; Neurons - drug effects; Neurons - physiology; Neurosciences; Original Investigation; Pharmacology/Toxicology; Prosencephalon - drug effects; Prosencephalon - physiology; Psychiatry; Receptors, GABA - metabolism; Receptors, GABA-A - metabolism; Receptors, Ionotropic Glutamate - agonists; Receptors, Ionotropic Glutamate - metabolism; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; Risk factors; RNA, Messenger - metabolism; Stem cells; Time Factors; Voltage-Gated Sodium Channels - metabolism; United Kingdom; Glutamate receptors; GABA; Ion channels; receptors; IPSC; Stem cells
• ISSN: 0033-3158; 1432-2072; 1432-2072
• DOI: 10.1007/s00213-013-3384-2

Introduction Genetic causes, or predisposition, are increasingly accepted to be part of the ethiopathogenesis of many neuropsychiatric diseases. While genes can be studied in any type of cells, their physiological function in human brain cells is difficult to evaluate, particularly in living subjects. Methods As a first step towards the characterisation of human inducible pluripotent stem cell (iPSC)-derived neurons from autism spectrum disorder (ASD) patients, we used gene expression and functional studies to define the regional identity of the typical forebrain differentiation, demonstrate expression patterns of genes of interest in ASD and understand the properties of ‘control’ iPSC-derived neurons (iCell-Neurons™), with a focus on receptors and ion channels that play a central role in synaptic physio-pathology. Results and discussion The gene expression profile of the iCell-Neurons™ closely resembled that observed in neonatal prefrontal cortex tissues. Functional studies, performed mainly using calcium flux assays, demonstrated the presence of ionotropic glutamate (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N -methyl- d -aspartate) and gamma-aminobutyric acid type A receptors. Voltage-gated sodium and calcium channels were also identified using similar techniques. Conclusions Overall, the results reported here suggest that iCell-Neurons™ are a good cellular model of a relatively immature forebrain human neuron population that can be used both as a control in comparison to patients cells, and as host cells in which mutations, insertions and deletions can be used in order to study the molecular mechanisms of ASD and other neurological disorders in an isogenic cellular background.