Human iPSC Neurons Display Activity-Dependent Neurotransmitter Secretion: Aberrant Catecholamine Levels in Schizophrenia Neurons

Summary This study investigated human-induced pluripotent stem cell (hiPSC) -derived neurons for their ability to secrete neurotransmitters in an activity-dependent manner, the fundamental property required for chemical neurotransmission. Cultured hiPSC neurons showed KCl stimulation of activity-dependent secretion of catecholamines—dopamine (DA), norepinephrine (NE), and epinephrine (Epi)—and the peptide neurotransmitters dynorphin and enkephlain. hiPSC neurons express the biosynthetic enzymes for catecholamines and neuropeptides. Because altered neurotransmission contributes to schizophrenia (SZ), we compared SZ to control cultures of hiPSC neurons and found that SZ cases showed elevated levels of secreted DA, NE, and Epi. Consistent with increased catecholamines, the SZ neuronal cultures showed a higher percentage of tyrosine hydroxylase (TH)-positive neurons, the first enzymatic step for catecholamine biosynthesis. These findings show that hiPSC neurons possess the fundamental property of activity-dependent neurotransmitter secretion and can be advantageously utilized to examine regulation of neurotransmitter release related to brain disorders.
Graphical Abstract
Highlights • hiPSC neurons show activity-dependent secretion of catecholamines and neuropeptides • hiPSC neurons express enzymes for production of catecholamines and neuropeptides • SZ hiPSC neurons show changes in catecholamines secreted • SZ hiPSC neuronal cultures display increased percentage of TH-positive neurons
In this article, Hook and colleagues show that human induced pluripotent stem cell (hiPSC) neurons possess the fundamental property of activity-dependent neurotransmitter secretion, and examination of several case studies of schizophrenia (SZ) patient-derived schizophrenia hiPSC neurons illustrate aberrant catecholamine neurotransmitters with increased percentage of tyrosine hydroxylase neurons.