GCP II (NAALADase) inhibition suppresses mossy fiber-CA3 synaptic neurotransmission by a presynaptic mechanism

J Neurophysiol. 2004 Jan;91(1):182-93. doi: 10.1152/jn.00465.2003. Epub 2003 Aug 13.


We tested the hypothesis that endogenous N-acetylaspartylglutamate (NAAG) presynaptically inhibits glutamate release at mossy fiber-CA3 synapses. For this purpose, we made use of 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA), an inhibitor of glutamate carboxypeptidase II [GCP II; also known as N-acetylated alpha-linked acidic dipeptidase (NAALADase)], the enzyme that hydrolyzes NAAG into N-acetylaspartate and glutamate. Application of 2-MPPA (1-20 microM) had no effect on intrinsic membrane properties of CA3 pyramidal neurons recorded in vitro in whole cell current- or voltage-clamp mode. Bath application of 10 microM 2-MPPA suppressed evoked excitatory postsynaptic current (EPSC) amplitudes. Attenuation of EPSC amplitudes was accompanied by a significant increase in paired-pulse facilitation (50-ms interpulse intervals), suggesting that a presynaptic mechanism is involved. The group II metabotropic glutamate receptor (mGluR) antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-y l) propanoic acid (LY341495) prevented the 2-MPPA-dependent suppression of EPSC amplitudes. 2-MPPA reduced the frequencies of TTX-insensitive miniature EPSCs (mEPSC), without affecting their amplitudes, further supporting a presynaptic action for GCP II inhibition. 2-MPPA-induced reduction of mEPSC frequencies was prevented by LY341495, reinforcing the role of presynaptic group II mGluR. Because GCP II inhibition is thought to increase NAAG levels, these results suggest that NAAG suppresses synaptic transmission at mossy fiber-CA3 synapses through presynaptic activation of group II mGluRs.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acids / pharmacology
  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Calcium / pharmacology
  • Chemokine CXCL6
  • Chemokines, CXC / antagonists & inhibitors*
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Electric Conductivity
  • Electric Stimulation
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Glutarates / pharmacology*
  • In Vitro Techniques
  • Male
  • Mossy Fibers, Hippocampal / drug effects*
  • Mossy Fibers, Hippocampal / physiology
  • Neural Inhibition / drug effects*
  • Neurons / drug effects
  • Neurons / physiology
  • Patch-Clamp Techniques
  • Presynaptic Terminals / drug effects*
  • Presynaptic Terminals / physiology
  • Probability
  • Rats
  • Sulfhydryl Compounds / pharmacology*
  • Synaptic Transmission / drug effects*
  • Synaptic Transmission / physiology
  • Time Factors
  • Xanthenes / pharmacology


  • 2-(3-mercaptopropyl)pentanedioic acid
  • Amino Acids
  • Chemokine CXCL6
  • Chemokines, CXC
  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • Glutarates
  • LY 341495
  • Sulfhydryl Compounds
  • Xanthenes
  • Calcium