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Specific inhibition of N-methyl-D-aspartate receptor function in rat hippocampal neurons by L-phenylalanine at concentrations observed during phenylketonuria

Molecular Psychiatry volume 7, pages 359–367 (2002)Cite this article

Abstract

Hippocampal N-methyl-D-aspartate receptors (NMDARs) are thought to be involved in the regulation of memory formation and learning. Investigation of NMDAR function during experimental conditions known to be associated with impaired cognition in vivo may provide new insights into the role of NMDARs in learning and memory. Specifically, the mechanism whereby high concentrations of L-phenylalanine (L-Phe) during phenylketonuria (>1.2 mM) cause mental retardation remains unknown. Therefore, the effects of L-Phe on NMDA-activated currents (INMDA) were studied in cultured hippocampal neurons from newborn rats using the patch-clamp technique. L-Phe specifically and reversibly attenuated INMDA in a concentration-dependent manner (IC50 = 1.71 ± 0.24 mM). In contrast, L-tyrosine (L-Tyr), an amino acid synthesized from L-Phe in normal subjects, did not significantly change INMDA. Although the L-Phe-INMDA concentration-response relationship was independent of the concentration of NMDA, it was shifted rightward by increasing the concentration of glycine. Consistent with an effect of L-Phe on the NMDAR glycine-binding site, L-Phe (1 mM) did not attenuate INMDA in the presence of D-alanine (10 μM). Furthermore, L-Phe significantly attenuated neither glutamate-activated current in the presence of MK-801, nor current activated by AMPA. The finding that L-Phe inhibits specifically NMDAR current in hippocampal neurons by competing for the glycine-binding site suggests a role for impaired NMDAR function in the development of mental retardation during phenylketonuria and accordingly an important role for NMDARs in memory formation and learning.

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Acknowledgements

This study was supported by funding from the University of Florida McKnight Brain Institute, Howard Hughes Medical Institute and JS Gravenstein Endowed Professorship.

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Authors and Affiliations

  1. Department of Anesthesiology, University of Florida, Gainsville, 32610-0254, FL, USA

    A V Glushakov, D M Dennis, T E Morey, R F Cucchiara, C N Seubert & A E Martynyuk

  2. Dept of Pharmacology & Experimental Therapeutics, University of Florida, Gainsville, 32610-0254, FL, USA

    D M Dennis

  3. Dept of Physiology, University of Florida, Gainsville, 32610-0254, FL, USA

    C Sumners

  4. Dept of Neuroscience, University of Florida, Gainesville, 32610–0254, FL, USA

    A E Martynyuk

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  1. A V Glushakov
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Correspondence to A E Martynyuk.

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Glushakov, A., Dennis, D., Morey, T. et al. Specific inhibition of N-methyl-D-aspartate receptor function in rat hippocampal neurons by L-phenylalanine at concentrations observed during phenylketonuria. Mol Psychiatry 7, 359–367 (2002). https://doi.org/10.1038/sj.mp.4000976

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