A presynaptic N-methyl-D-aspartate autoreceptor in rat hippocampus modulating amino acid release from a cytoplasmic pool

Eur J Neurosci. 1998 Jan;10(1):106-14. doi: 10.1046/j.1460-9568.1998.00008.x.


A possible role of the N-methyl-D-aspartate receptor (NMDA-R) as a presynaptic autoreceptor was investigated using Percoll-purified hippocampus nerve terminals (synaptosomes). This preparation contained only a neglectable amount of postsynaptic structures. Two main effects of NMDA were observed. First, NMDA dose-dependently (10-100 microM) and in the absence of Mg2+, stimulated basal release of aspartate and glutamate, but not of GABA. MK801 (10 microM), an open NMDA-R-channel blocker, reduced this effect even below control levels, indicating endogenous NMDA-R activation. By superfusing synaptosomes, which prevents a tonic receptor occupation, also basal GABA release was stimulated by NMDA. The NMDA-induced potentiation of amino acid superfusate levels was blocked both by MK801 and Mg2+ (1 mM), was slow in onset and returned to baseline after NMDA-removal. The NMDA-effect was also found in the absence of extracellular Ca2+, suggesting that amino acids were released from a non-vesicular (cytoplasmic) pool. Secondly, in KCl-depolarized synaptosomes exposed to 1 mM Mg2+, NMDA did not affect the release of the amino acids. MK801, however, reduced the KCl-evoked Ca2+-independent release of aspartate and glutamate, but not of GABA. L-trans-PDC, the selective inhibitor of the glutamate/aspartate transporter, prevented this MK801-effect, suggesting a coupling between NMDA-Rs and these transporters. These data provide evidence for a presynaptic NMDA autoreceptor in rat hippocampus. We speculate on the role of this NMDA-R to depolarize the presynaptic membrane by Na+-entry, which may induce reversal of amino acid transporters and thereby releasing amino acids from a cytoplasmic pool.

MeSH terms

  • Animals
  • Aspartic Acid / metabolism
  • Autoreceptors / physiology*
  • Calcium / metabolism
  • Cytoplasm / metabolism
  • Dizocilpine Maleate / pharmacology
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Antagonists / pharmacology
  • Glutamic Acid / metabolism
  • Hippocampus / chemistry
  • Hippocampus / metabolism*
  • Ion Channel Gating / drug effects
  • Magnesium / pharmacology
  • Male
  • Microscopy, Electron
  • Neurotransmitter Agents / metabolism*
  • Potassium Chloride / pharmacology
  • Presynaptic Terminals / chemistry*
  • Presynaptic Terminals / drug effects
  • Rats
  • Rats, Wistar
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Synaptosomes / chemistry
  • Synaptosomes / ultrastructure
  • gamma-Aminobutyric Acid / metabolism


  • Autoreceptors
  • Excitatory Amino Acid Antagonists
  • Neurotransmitter Agents
  • Receptors, N-Methyl-D-Aspartate
  • Aspartic Acid
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • Potassium Chloride
  • Dizocilpine Maleate
  • Magnesium
  • Calcium