A Single-Cell Model for Synaptic Transmission and Plasticity in Human iPSC-Derived Neurons

Cell Rep. 2019 May 14;27(7):2199-2211.e6. doi: 10.1016/j.celrep.2019.04.058.

Abstract

Synaptic dysfunction is associated with many brain disorders, but robust human cell models to study synaptic transmission and plasticity are lacking. Instead, current in vitro studies on human neurons typically rely on spontaneous synaptic events as a proxy for synapse function. Here, we describe a standardized in vitro approach using human neurons cultured individually on glia microdot arrays that allow single-cell analysis of synapse formation and function. We show that single glutamatergic or GABAergic forebrain neurons differentiated from human induced pluripotent stem cells form mature synapses that exhibit robust evoked synaptic transmission. These neurons show plasticity features such as synaptic facilitation, depression, and recovery. Finally, we show that spontaneous events are a poor predictor of synaptic maturity and do not correlate with the robustness of evoked responses. This methodology can be deployed directly to evaluate disease models for synaptic dysfunction and can be leveraged for drug development and precision medicine.

Keywords: NGN2; forward programming; human neuron; iPSC; single-cell model; synapse; synaptic dysfunction; synaptic plasticity; synaptic transmission; synaptopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cells, Cultured
  • Excitatory Amino Acid Agents / pharmacology
  • GABAergic Neurons / cytology
  • GABAergic Neurons / metabolism*
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / metabolism*
  • Mice
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurogenesis / drug effects
  • Neurogenesis / genetics*
  • Neurogenesis / physiology
  • Neuroglia / cytology
  • Neuroglia / physiology
  • Neuronal Plasticity / physiology*
  • Rats
  • Single-Cell Analysis / methods*
  • Synapses / physiology
  • Synaptic Transmission / physiology*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Excitatory Amino Acid Agents
  • NEUROG2 protein, human
  • Nerve Tissue Proteins