Networks of Cultured iPSC-Derived Neurons Reveal the Human Synaptic Activity-Regulated Adaptive Gene Program

Cell Rep. 2017 Jan 3;18(1):122-135. doi: 10.1016/j.celrep.2016.12.018.


Long-term adaptive responses in the brain, such as learning and memory, require synaptic activity-regulated gene expression, which has been thoroughly investigated in rodents. Using human iPSC-derived neuronal networks, we show that the human and the mouse synaptic activity-induced transcriptional programs share many genes and both require Ca2+-regulated synapse-to-nucleus signaling. Species-specific differences include the noncoding RNA genes BRE-AS1 and LINC00473 and the protein-coding gene ZNF331, which are absent in the mouse genome, as well as several human genes whose orthologs are either not induced by activity or are induced with different kinetics in mice. These results indicate that lineage-specific gain of genes and DNA regulatory elements affects the synaptic activity-regulated gene program, providing a mechanism driving the evolution of human cognitive abilities.

Keywords: HIC1; NMDA receptor; calcium signaling; genome-wide; human adaptogenomics; human neurons; neuronal networks; species specificity; transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Aminopyridine / pharmacology
  • Animals
  • Base Sequence
  • Bicuculline / pharmacology
  • Calcium Signaling / drug effects
  • Cell Line
  • Cell Lineage / drug effects
  • Cells, Cultured
  • Electrophysiological Phenomena / drug effects
  • Gene Expression Regulation* / drug effects
  • Genes, Immediate-Early
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / metabolism*
  • Mice
  • Neurons / cytology*
  • Neurons / drug effects
  • Neurons / metabolism*
  • Promoter Regions, Genetic / genetics
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Species Specificity
  • Synapses / drug effects
  • Synapses / metabolism*


  • 4-Aminopyridine
  • Bicuculline