title: Maturation of AMPAR composition and the GABAAR reversal potential in hPSC-derived cortical neurons.
abstract: 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.
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom; and Euan MacDonald Centre for MND Research, Centre for Clinical Brain Sciences, and MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Livesey
authors.forename: Bilada
authors.initials: B
authors.lastname: Bilican
authors.forename: Jing
authors.initials: J
authors.lastname: Qiu
authors.forename: Nina M
authors.initials: NM
authors.lastname: Rzechorzek
authors.forename: Ghazal
authors.initials: G
authors.lastname: Haghi
authors.forename: Karen
authors.initials: K
authors.lastname: Burr
authors.forename: Giles E
authors.initials: GE
authors.lastname: Hardingham
authors.forename: Siddharthan
authors.initials: S
authors.lastname: Chandran
authors.forename: David J A
authors.initials: DJ
authors.lastname: Wyllie
mesh_terms: D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D002540:Cerebral Cortex / Q000166:cytology*; D053595:Embryonic Stem Cells / Q000166:cytology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D009474:Neurons / Q000166:cytology* / Q000502:physiology*; D018408:Patch-Clamp Techniques; D039904:Pluripotent Stem Cells / Q000166:cytology*; D018091:Receptors, AMPA / Q000235:genetics / Q000502:physiology*; D011963:Receptors, GABA-A / Q000235:genetics / Q000502:physiology*; D064506:Solute Carrier Family 12, Member 2 / Q000235:genetics / Q000502:physiology; D027981:Symporters / Q000235:genetics / Q000502:physiology; D000096922:K Cl- Cotransporters
chemical_list: D018091:Receptors, AMPA; D011963:Receptors, GABA-A; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters; D000096922:K Cl- Cotransporters; C578877:SLC12A2 protein, human; C104723:glutamate receptor ionotropic, AMPA 3; C104724:glutamate receptor ionotropic, AMPA 4; C104722:glutamate receptor ionotropic, AMPA 2
keywords: GABA; glutamate; neurotransmitter; patch clamp; qRT-PCR; stem cells