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

Change log
Turner-Bridger, Benita  ORCID logo
Peter, Manuel 
Momoh, Ayiba 
Arambepola, Devika 

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.

Cerebral cortex, Human, Networks, Neural development, Stem cells, Cerebral Cortex, Dendritic Spines, Humans, Image Processing, Computer-Assisted, In Vitro Techniques, Microscopy, Fluorescence, Nerve Net, Neuronal Plasticity, Patch-Clamp Techniques, Pluripotent Stem Cells, Reverse Transcriptase Polymerase Chain Reaction, Single-Cell Analysis, Video Recording
Journal Title
Conference Name
Journal ISSN
Volume Title
The Company of Biologists
Wellcome Trust (092096/Z/10/Z)
Wellcome Trust (101052/Z/13/Z)
Cancer Research Uk (None)
Medical Research Council (MR/L023784/2)
Medical Research Council (MR/L023784/1)