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Brain Advance Access published online on January 5, 2005
Brain, doi:10.1093/brain/awh354
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Brain © Guarantors of Brain 2005; all rights reserved
Received August 2, 2004
Revised October 8, 2004
Accepted October 14, 2004

Article

Long-term changes in glutamatergic synaptic transmission in phenylketonuria

A. V. Glushakov 1, O. Glushakova 2, M. Varshney 1, L. K. Bajpai 1, C. Sumners 3, P. J. Laipis 4, J. E. Embury 4, S. P. Baker 5, D. H. Otero 5, D. M. Dennis 6, C. N. Seubert 1, and A. E. Martynyuk 6*

1 Departments of Anesthesiology, University of Florida, Gainesville, FL, USA
2 Departments of Medicine, University of Florida, Gainesville, FL, USA
3 Departments of Physiology and Functional Genomics, University of Florida, Gainesville, FL, USA; McKnight Brain Institute, University of Florida, Gainesville, FL, USA
4 Departments of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, USA
5 Departments of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA
6 Departments of Anesthesiology, University of Florida, Gainesville, FL, USA; McKnight Brain Institute, University of Florida, Gainesville, FL, USA

* To whom correspondence should be addressed.
A. E. Martynyuk, E-mail: AMartynyuk{at}anest.ufl.edu


  Abstract

Summary The cellular mechanisms that underlie impaired brain function during phenylketonuria (PKU), the most common biochemical cause of mental retardation in humans, remain unclear. Acute application of L-Phe at concentrations observed in the PKU brain depresses glutamatergic synaptic transmission but does not affect GABA receptor activity in cultured neurons. If these depressant effects of L-Phe take place in the PKU brain, then chronic impairment of the glutamate system, which may contribute to impaired brain function, could be detected as changes in postsynaptic glutamate receptors. This hypothesis was tested by using a combination of liquid chromatography- mass spectrometry, patch-clamp, radioligand binding and western blot approaches in forebrain tissue from heterozygous and homozygous (PKU) Pahenu2 mice. Brain concentrations of L-Phe were nearly six-fold greater in PKU mice (863.12 ± 17.96 µmol/kg) than in their heterozygous counterparts (149.32 ± 10.23 µmol/kg). This concentration is significantly higher than the KB of 573 µM for L-Phe to compete for N-methyl-D-aspartate (NMDA) receptors. Receptor binding experiments with [3H]MK-801 showed significant up-regulation of NMDA receptor density in PKU mice. Consistent with the depressant effects of L-Phe, expression of NMDA receptor NR2A and (RS)-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor Glu1 and Glu2/3 subunits was significantly increased, whereas expression of the NR2B subunit was decreased. There was no change in GABA {alpha}1 subunit expression. Given the role of the glutamatergic system in brain development and function, these changes may, at least in part, explain the brain disorders associated with PKU.

Keywords: phenylketonuria; NMDA receptor; AMPA receptor; Pahenu2 mice; mental retardation.
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