Maturation of AMPAR composition and the GABAAR reversal potential in hPSC-derived cortical neurons

• Published in: The Journal of neuroscience Vol. 34; no. 11; pp. 4070 - 4075
• Main Authors: Livesey, Matthew R, Bilican, Bilada, Qiu, Jing, Rzechorzek, Nina M, Haghi, Ghazal, Burr, Karen, Hardingham, Giles E, Chandran, Siddharthan, Wyllie, David J A
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 12.03.2014
• Subjects: Brief Communications; Cell Differentiation - physiology; Cell Line; Cerebral Cortex - cytology; Embryonic Stem Cells - cytology; Excitatory Postsynaptic Potentials - physiology; Female; Humans; K Cl- Cotransporters; Male; Neurons - cytology; Neurons - physiology; Patch-Clamp Techniques; Pluripotent Stem Cells - cytology; Receptors, AMPA - genetics; Receptors, AMPA - physiology; Receptors, GABA-A - genetics; Receptors, GABA-A - physiology; Solute Carrier Family 12, Member 2 - genetics; Solute Carrier Family 12, Member 2 - physiology; Symporters - genetics; Symporters - physiology; GABA; stem cells; patch clamp; neurotransmitter; glutamate; qRT-PCR
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.5410-13.2014

Rodent-based studies have shown that neurons undergo major developmental changes to ion channel expression and ionic gradients that determine their excitation-inhibition balance. Neurons derived from human pluripotent stem cells theoretically offer the potential to study classical developmental processes in a human-relevant system, although this is currently not well explored. Here, we show that excitatory cortical-patterned neurons derived from multiple human pluripotent stem cell lines exhibit native-like maturation changes in AMPAR composition such that there is an increase in the expression of GluA2(R) subunits. Moreover, we observe a dynamic shift in intracellular Cl- levels, which determines the reversal potential of GABAAR-mediated currents and is influenced by neurotrophic factors. The shift is concomitant with changes in KCC2 and NKCC1 expression. Because some human diseases are thought to involve perturbations to AMPAR GluA2 content and others in the chloride reversal potential, human stem-cell-derived neurons represent a valuable tool for studying these fundamental properties.