Development and function of human cerebral cortex neural networks from pluripotent stem cells in vitro
The Wellcome Trust / Cancer Research UK Gurdon Institute, University of Cambridge.
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Kirwan, P., Turner-Bridger, B., Peter, M., Momoh, A., Arambepola, D., Robinson, H., & Livesey, F. (2015). Development and function of human cerebral cortex neural networks from pluripotent stem cells in vitro. Development, 142 3178-3187. https://doi.org/10.1242/dev.123851
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 rabies-based 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.
Wellcome Trust (092096/Z/10/Z)
WELLCOME TRUST (101052/2/13/Z)
Cancer Research UK (A14492)
External DOI: https://doi.org/10.1242/dev.123851
This record's URL: https://www.repository.cam.ac.uk/handle/1810/249131
Creative Commons Attribution 4.0
Licence URL: http://creativecommons.org/licenses/by/4.0/