Endogenous N-acetylaspartylglutamate reduced NMDA receptor-dependent current neurotransmission in the CA1 area of the hippocampus.
N-Acetylaspartylglutamate (NAAG) is a neuropeptide found in high concentrations in the brain. Using whole-cell recordings of CA1 pyramidal neurons in acute hippocampal slices, we found that either (i) the application of exogenous NAAG or (ii) an increase of endogenous extracellular NAAG, caused by the inhibition of its catabolic enzyme glutamate carboxypeptidase II (GCP II), resulted in a significant reduction in the amplitude of the isolated NMDA receptor (NMDAR) component of the evoked excitatory postsynaptic current (EPSC). Conversely, reduction of endogenous extracellular NAAG caused by either (i) perfusion with a soluble form of pure human GCP II or (ii) affinity purified antibodies against NAAG, enhanced the amplitude of the isolated NMDAR current. Bath application of GCP II inhibitor induced a progressive loss of spontaneous NMDAR miniatures. Furthermore, NAAG blocked the induction of long-term potentiation at Schaffer collateral axons-CA1 pyramidal neuron synapses. All together, these results suggest that NAAG acts as an endogenous modulator of NMDARs in the CA1 area of the hippocampus.
Bergeron
Richard
R
Ottawa Health Research Institute, Department of Psychiatry, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada. rbergeron@ohri.ca
Imamura
Yukio
Y
Frangioni
John V
JV
Greene
Robert W
RW
Coyle
Joseph T
JT
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D054427:Chemokine CXCL6; D019743:Chemokines, CXC / Q000378:metabolism / Q000494:pharmacology; D004151:Dipeptides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D004347:Drug Interactions; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D020318:Rats, Long-Evans; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*
C402107:2-(phosphonomethyl)pentanedioic acid; D000906:Antibodies; C515503:CXCL6 protein, human; D054427:Chemokine CXCL6; D019743:Chemokines, CXC; D004151:Dipeptides; D018691:Excitatory Amino Acid Antagonists; D009943:Organophosphorus Compounds; D016194:Receptors, N-Methyl-D-Aspartate; C027172:isospaglumic acid; D015763:2-Amino-5-phosphonovalerate