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L‐phenylalanine selectively depresses currents at glutamatergic excitatory synapses
Author(s) -
Glushakov A.V.,
Dennis D.M.,
Sumners C.,
Seubert C.N.,
Martynyuk A.E.
Publication year - 2003
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.10569
Subject(s) - nmda receptor , glutamatergic , excitatory postsynaptic potential , glutamate receptor , glycine , neurotransmission , chemistry , 2 amino 5 phosphonovalerate , biophysics , neuroscience , glutamic acid , ampa receptor , agonist , biology , biochemistry , amino acid , receptor , excitatory amino acid antagonists
To explore the hypothesis that L‐phenylalanine (L‐Phe) depresses glutamatergic synaptic transmission and thus contributes to brain dysfunction in phenylketonuria (PKU), the effects of L‐Phe on spontaneous and miniature excitatory postsynaptic currents (s/mEPSCs) in rat and mouse hippocampal and cerebrocortical cultured neurons were studied using the patch‐clamp technique. L‐Phe depressed the amplitude and frequency of both N‐methyl‐D‐aspartate (NMDA) and non‐NMDA components of glutamate receptor (GluR) s/mEPSCs. The IC 50 of L‐Phe to inhibit non‐NMDAR mEPSC frequency was 0.98 ± 0.13 mM, a brain concentration seen in classical PKU. In contrast, D‐Phe had a significantly smaller effect, whereas L‐leucine, an amino acid that competes with L‐Phe for brain transporter, had no effect on mEPSCs. Unlike GluR s/mEPSCs, GABA receptor mIPSCs were not attenuated by L‐Phe. A high extracellular concentration of glycine prevented the attenuation by L‐Phe of NMDAR current, activated by exogenous agonist, and of NMDAR s/mEPSC amplitude, but not of NMDAR s/mEPSC frequency. On the other hand, L‐Phe significantly depressed non‐NMDAR current activated by low but not high concentrations of exogenous agonists. Glycine‐independent attenuation of NMDAR s/mEPSC frequency suggests decreased presynaptic glutamate release caused by L‐Phe, whereas decreased amplitudes of NMDAR and non‐NMDAR s/mEPSCs are consistent with competition of L‐Phe for the glycine‐ and glutamate‐binding sites of NMDARs and non‐NMDARs, respectively. The finding that GluR activity is significantly depressed at conditions characteristic of classical PKU indicates a potentially important contribution of impaired GluR function to PKU‐related mental retardation and provides important insights into the potential physiological consequences of impaired GluR function. © 2003 Wiley‐Liss, Inc.