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Human iPSC-Derived Neurons with Reliable Synapses and Large Presynaptic Action Potentials.

Torsten Bullmann1, Thomas Kaas1, Andreas Ritzau-Jost1

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The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|May 9, 2024
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Summary
This summary is machine-generated.

Researchers generated human neurons to study synaptic transmission. They discovered that human presynaptic action potentials are rapid and large, influencing glutamate release in the brain.

Keywords:
action potentialhumaniPSCpresynaptic

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Area of Science:

  • Neuroscience
  • Cell Biology
  • Molecular Biology

Background:

  • Understanding human brain function necessitates characterizing synaptic transmission in human neurons.
  • Presynaptic action potential properties, crucial for neurotransmitter release, remain controversial in human neurons.
  • Previous measurements lacked high temporal resolution in human neurons.

Purpose of the Study:

  • To determine the properties of presynaptic action potentials in human neurons.
  • To establish a model system for studying human glutamatergic synaptic transmission.
  • To investigate mechanisms of synchronous high-frequency glutamate release.

Main Methods:

  • Generated human glutamatergic neurons from pluripotent stem cells via Neurogenin 2 (Ngn2) expression.
  • Utilized super-resolution microscopy to visualize pre- and postsynaptic protein alignment.
  • Performed direct presynaptic patch-clamp recordings from mature human neurons.

Main Results:

  • Ngn2-induced human neurons showed decreased multiple axon initial segments and increased axonal tau and excitability with maturation.
  • Synaptic transmission was reliable at high frequencies (20-100 Hz) with increasing synchronicity over 9 weeks.
  • Direct recordings revealed human presynaptic action potentials with large overshoots (~25 mV) and short durations (~0.5 ms).

Conclusions:

  • Ngn2-induced neurons provide an effective model for high spatiotemporal resolution analysis of human glutamatergic synaptic transmission.
  • The findings predict that human brain glutamatergic transmission involves large, rapid presynaptic action potentials.
  • This study offers crucial insights into fundamental mechanisms of neurotransmission in the human brain.