Skip Navigation


Brain Advance Access originally published online on January 5, 2005
Brain 2005 128(2):300-307; doi:10.1093/brain/awh354
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
128/2/300    most recent
awh354v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (6)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Glushakov, A. V.
Right arrow Articles by Martynyuk, A. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Glushakov, A. V.
Right arrow Articles by Martynyuk, A. E.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Brain Vol. 128 No. 2 © Guarantors of Brain 2005; all rights reserved

Long-term changes in glutamatergic synaptic transmission in phenylketonuria

A. V. Glushakov1, O. Glushakova2, M. Varshney1, L. K. Bajpai1, C. Sumners3,6, P. J. Laipis4, J. E. Embury4, S. P. Baker5, D. H. Otero5, D. M. Dennis1,6, C. N. Seubert1 and A. E. Martynyuk1,6

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

Correspondence to: Anatoly E. Martynyuk, PhD, Department of Anesthesiology, University of Florida, P.O. Box 100254, JHMHC, 1600 SW Archer Road, Gainesville, FL 32610-0254, USA E-mail: AMartynyuk{at}anest.ufl.edu

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.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.