Modulation of NMDA receptor current in layer V pyramidal neurons of the rat prefrontal cortex by P2Y receptor activation

Kerstin Wirkner, Albrecht Günther, Marco Weber, Segundo J. Guzman, Thomas Krause, Jochen Fuchs, Laszlo Köles, Wolfgang Nörenberg, Peter Illes

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Current responses to N-methyl-D-aspartate (NMDA) in layer V pyramidal neurons of the rat prefrontal cortex were potentiated by the P2 receptor agonists adenosine 5′-triphosphate (ATP) and uridine 5′-triphosphate (UTP). The failure of these nucleotides to induce inward current on fast local superfusion suggested the activation of P2Y rather than P2X receptors. The potentiation by ATP persisted in a Ca2+-free superfusion medium but was abolished by 1,2-bis(2-amino-5-fluorophenoxy)ethane-N,N,N′,N′- tetraacetic acid tetrakis(acetoxymethyl) ester, cyclopiazonic acid, 7-nitroindazole, fluoroacetic acid, bafilomycin, and tetanus toxin, indicating that an astrocytic signaling molecule may participate. Because the metabotropic glutamate receptor (mGluR) agonists (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) (group I/II) and (RS)-3,5-dihydroxyphenylglycine (group I) both imitated the effect of ATP and the group I mGluR antagonist 1-aminoindan-1,5- dicarboxylic acid or a combination of selective mGluR1 (7-(hydroxyimino)-cyclopropa[b]chromen-1a-carboxylate) and mGluR5 (2-methyl-6-(phenylethynyl)pyridine) antagonists abolished the facilitation by ATP, it was concluded that the signaling molecule may be glutamate. Pharmacological tools known to interfere with the transduction cascade of type I mGluRs (guanosine 5′-O-(3-thiodiphosphate), U-73122, xestospongin C, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid, calmodulin kinase II [CAMKII] inhibitor peptide) depressed the actions of both ATP and ACPD. Characterization of the P2Y receptor by agonists (ATP and UTP), antagonists (suramin and pyridoxal-phosphate-6-azophenyl-2′,4′- disulfonic acid), and knockout mice (P2Y2-/-) suggested that the nucleotides act at the P2Y4 subtype. In conclusion, we propose that exogenous and probably also endogenous ATP release vesicular glutamate from astrocytes by P2Y4 receptor activation. This glutamate then stimulates type I mGluRs of layer V pyramidal neurons and via the G q/phospholipase C/inositol 1,4,5-trisphosphate/Ca2+/CAMKII transduction pathway facilitates NMDA receptor currents.

Original languageEnglish
Pages (from-to)621-631
Number of pages11
JournalCerebral Cortex
Issue number3
Publication statusPublished - Mar 1 2007



  • Astrocyte
  • NMDA receptor
  • P2 receptor
  • Pyramidal neuron
  • Rat prefrontal cortex

ASJC Scopus subject areas

  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience

Cite this

Wirkner, K., Günther, A., Weber, M., Guzman, S. J., Krause, T., Fuchs, J., Köles, L., Nörenberg, W., & Illes, P. (2007). Modulation of NMDA receptor current in layer V pyramidal neurons of the rat prefrontal cortex by P2Y receptor activation. Cerebral Cortex, 17(3), 621-631.