Modulation of glutamate mobility reveals the mechanism underlying slow-rising AMPAR EPSCs and the diffusion coefficient in the synaptic cleft

Neuron. 2004 Jun 10;42(5):757-71. doi: 10.1016/j.neuron.2004.04.003.


Fast- and slow-rising AMPA receptor-mediated EPSCs occur at central synapses. Fast-rising EPSCs are thought to be mediated by rapid local release of glutamate. However, two controversial mechanisms have been proposed to underlie slow-rising EPSCs: prolonged local release of transmitter via a fusion pore, and spillover of transmitter released rapidly from distant sites. We have investigated the mechanism underlying slow-rising EPSCs and the diffusion coefficient of glutamate in the synaptic cleft (Dglut) at cerebellar mossy fiber-granule cell synapses using a combination of diffusion modeling and patch-clamp recording. Simulations show that modulating Dglut has different effects on the peak amplitudes and time courses of EPSCs mediated by these two mechanisms. Slowing diffusion with the macromolecule dextran slowed slow-rising EPSCs and had little effect on their amplitude, indicating that glutamate spillover underlies these currents. Our results also suggest that under control conditions Dglut is approximately 3-fold lower than in free solution.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / pharmacology
  • Animals
  • Animals, Newborn
  • Benzylamines / pharmacology
  • Cerebellum / cytology
  • Cerebellum / physiology
  • Computer Simulation
  • Dextrans / pharmacology
  • Diffusion*
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology*
  • Glutamic Acid / metabolism*
  • In Vitro Techniques
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Nerve Fibers / physiology
  • Neurons / physiology
  • Patch-Clamp Techniques / methods
  • Phosphinic Acids / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Reaction Time
  • Receptors, AMPA / physiology*
  • Synapses / classification
  • Synapses / drug effects
  • Synapses / physiology*
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology*
  • Time Factors
  • Xanthenes / pharmacology


  • Amino Acids
  • Benzylamines
  • Dextrans
  • Excitatory Amino Acid Antagonists
  • LY 341495
  • Phosphinic Acids
  • Receptors, AMPA
  • Xanthenes
  • CGP 52432
  • Glutamic Acid