Abstract
Neural progenitors differentiated from induced pluripotent stem cells (iPS) hold potentials for treating neurological diseases. Serotonin has potent effects on neuronal functions through multiple receptors, underlying a variety of neural disorders. Glutamate and GABA receptors have been proven functional in neurons differentiated from iPS, however, little is known about 5-HT receptor-mediated modulation in such neuronal networks. In the present study, human iPS were differentiated into cells possessing featured physiological properties of cortical neurons. Whole-cell patch-clamp recording was used to examine the involvement of 5-HT2 receptors in functional modulation of GABAergic synaptic transmission. We found that serotonin and DOI (a selective agonist of 5-HT2A/C receptor) reversibly reduced GABA-activated currents, and this 5-HT2A/C receptor mediated inhibition required G protein, PLC, PKC, and Ca2+ signaling. Serotonin increased the frequency of miniature inhibitory postsynaptic currents (mIPSCs), which could be mimicked by α-methylserotonin, a 5-HT2 receptor agonist. In contrast, DOI reduced both frequency and amplitude of mIPSCs. These findings suggested that in iPS-derived human neurons serotonin postsynaptically reduced GABAa receptor function through 5-HT2A/C receptors, but presynaptically other 5-HT2 receptors counteracted the action of 5-HT2A/C receptors. Functional expression of serotonin receptors in human iPS-derived neurons provides a pre-requisite for their normal behaviors after grafting.
Highlights
The development and function of the cerebral cortex is subjected to massive monoaminegic modulation
Neural progenitor cells (NPCs) were derived from human induced pluripotent stem cells (iPS) reprogrammed from urine cells (UC5) or fibroblasts (GZ2) as described before[27,28], as well as embryonic stem cell (ES) (H1) as a control
The majority of the results shown here were obtained from iPS line UC5, which was derived by using a feeder-free, serum-free and virus-free method without oncogene c-MYC, representing a more promising translational application for regenerative medicine
Summary
The development and function of the cerebral cortex is subjected to massive monoaminegic modulation. Amounting evidences revealed the existence of glutamate and GABA receptors in neural stem cell derived neurons[1,2] and even the role of neuromodulators in the proliferation and differentiation of neural stem cells[20,21]; few studies addressed the neuromodulation mediated by serotonin and its receptors. Functional expression of serotonin receptors in human iPS-derived neurons would endow them with the ability to receive normal serotonergic modulation from the host after grafting, and to serve as a cell model to screen serotonin related neuropsychological drugs. We differentiated iPS into forebrain-like cortical neurons, and whole-cell patch-clamp recording technique was adopted to investigate the involvement of 5-HT2 receptors in the modulation of GABAa receptor function and inhibitory synaptic transmissions
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