Development and function of human cerebral cortex neural networks from pluripotent stem cells in vitro

Peter Kirwan, Benita Turner-Bridger, Manuel Peter, Ayiba Momoh, Devika Arambepola, Hugh P.C. Robinson, Frederick J. Livesey*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

92 Citations (Scopus)

Abstract

A key aspect of nervous system development, including that of the cerebral cortex, is the formation of higher-order neural networks. Developing neural networks undergo several phases with distinct activity patterns in vivo, which are thought to prune and fine-tune network connectivity.We report here that human pluripotent stem cell (hPSC)-derived cerebral cortex neurons form large-scale networks that reflect those found in the developing cerebral cortex in vivo. Synchronised oscillatory networks develop in a highly stereotyped pattern over several weeks in culture. An initial phase of increasing frequency of oscillations is followed by a phase of decreasing frequency, before giving rise to non-synchronous, ordered activity patterns. hPSC-derived cortical neural networks are excitatory, driven by activation of AMPA- and NMDA-type glutamate receptors, and can undergo NMDA-receptor-mediated plasticity. Investigating single neuron connectivity within PSC-derived cultures, using rabiesbased trans-synaptic tracing, we found two broad classes of neuronal connectivity: most neurons have small numbers (<10) of presynaptic inputs, whereas a small set of hub-like neurons have large numbers of synaptic connections (>40). These data demonstrate that the formation of hPSC-derived cortical networks mimics in vivo cortical network development and function, demonstrating the utility of in vitro systems for mechanistic studies of human forebrain neural network biology.

Original languageEnglish
Pages (from-to)3178-3187
Number of pages10
JournalDevelopment (Cambridge)
Volume142
Issue number18
DOIs
Publication statusPublished - 23 Sept 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2015, Published by The Company of Biologists Ltd.

Keywords

  • Cerebral cortex
  • Human
  • Networks
  • Neural development
  • Stem cells

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