Complex alteration of NMDA receptors in transgenic Huntington's disease mouse brain: analysis of mRNA and protein expression, plasma membrane association, interacting proteins, and phosphorylation

Ruth Luthi-Carter; Barbara L Apostol; Anthone W Dunah; Molly M DeJohn; Laurie A Farrell; Gillian P Bates; Anne B Young; David G Standaert; Leslie M Thompson; Jang-Ho J Cha

Neurobiology of Disease (Dec 2003)

Complex alteration of NMDA receptors in transgenic Huntington's disease mouse brain: analysis of mRNA and protein expression, plasma membrane association, interacting proteins, and phosphorylation

Ruth Luthi-Carter,
Barbara L Apostol,
Anthone W Dunah,
Molly M DeJohn,
Laurie A Farrell,
Gillian P Bates,
Anne B Young,
David G Standaert,
Leslie M Thompson,
Jang-Ho J Cha

Affiliations

Ruth Luthi-Carter: MassGeneral Institute for Neurodegenerative Diseases, B114-2000, 114 16th Street, Charlestown, MA 02129-4404, USA; Department of Psychiatry and Human Behavior, Gillespie 2121, University of California, Irvine, CA, 92697-4260, USA; Division of Medical and Molecular Genetics, GKT School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK
Barbara L Apostol: MassGeneral Institute for Neurodegenerative Diseases, B114-2000, 114 16th Street, Charlestown, MA 02129-4404, USA; Department of Psychiatry and Human Behavior, Gillespie 2121, University of California, Irvine, CA, 92697-4260, USA; Division of Medical and Molecular Genetics, GKT School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK
Anthone W Dunah: MassGeneral Institute for Neurodegenerative Diseases, B114-2000, 114 16th Street, Charlestown, MA 02129-4404, USA; Department of Psychiatry and Human Behavior, Gillespie 2121, University of California, Irvine, CA, 92697-4260, USA; Division of Medical and Molecular Genetics, GKT School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK
Molly M DeJohn: MassGeneral Institute for Neurodegenerative Diseases, B114-2000, 114 16th Street, Charlestown, MA 02129-4404, USA; Department of Psychiatry and Human Behavior, Gillespie 2121, University of California, Irvine, CA, 92697-4260, USA; Division of Medical and Molecular Genetics, GKT School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK
Laurie A Farrell: MassGeneral Institute for Neurodegenerative Diseases, B114-2000, 114 16th Street, Charlestown, MA 02129-4404, USA; Department of Psychiatry and Human Behavior, Gillespie 2121, University of California, Irvine, CA, 92697-4260, USA; Division of Medical and Molecular Genetics, GKT School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK
Gillian P Bates: MassGeneral Institute for Neurodegenerative Diseases, B114-2000, 114 16th Street, Charlestown, MA 02129-4404, USA; Department of Psychiatry and Human Behavior, Gillespie 2121, University of California, Irvine, CA, 92697-4260, USA; Division of Medical and Molecular Genetics, GKT School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK
Anne B Young: MassGeneral Institute for Neurodegenerative Diseases, B114-2000, 114 16th Street, Charlestown, MA 02129-4404, USA; Department of Psychiatry and Human Behavior, Gillespie 2121, University of California, Irvine, CA, 92697-4260, USA; Division of Medical and Molecular Genetics, GKT School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK
David G Standaert: MassGeneral Institute for Neurodegenerative Diseases, B114-2000, 114 16th Street, Charlestown, MA 02129-4404, USA; Department of Psychiatry and Human Behavior, Gillespie 2121, University of California, Irvine, CA, 92697-4260, USA; Division of Medical and Molecular Genetics, GKT School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK
Leslie M Thompson: MassGeneral Institute for Neurodegenerative Diseases, B114-2000, 114 16th Street, Charlestown, MA 02129-4404, USA; Department of Psychiatry and Human Behavior, Gillespie 2121, University of California, Irvine, CA, 92697-4260, USA; Division of Medical and Molecular Genetics, GKT School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK
Jang-Ho J Cha: MassGeneral Institute for Neurodegenerative Diseases, B114-2000, 114 16th Street, Charlestown, MA 02129-4404, USA; Department of Psychiatry and Human Behavior, Gillespie 2121, University of California, Irvine, CA, 92697-4260, USA; Division of Medical and Molecular Genetics, GKT School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK

Journal volume & issue: Vol. 14, no. 3
pp. 624 – 636

Abstract

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We analyzed NMDA receptor subunit mRNAs, proteins, and anchoring proteins in mice transgenic for exon 1 of the HD gene. R6/2 mice had decreased levels of mRNAs encoding ε1 and ε2 NMDA receptor subunits (mouse orthologs of rat NR2A and NR2B subunits), but not the ζ1 subunit (mouse ortholog of NR1), as assessed by gene expression profiling and Northern blotting. In situ hybridization resolved mRNA decreases spatially to the CA1 field of hippocampus. Western blotting revealed decreases in plasma membrane-associated ε1 and ε2 subunits in hippocampus, and decreases in plasma membrane-associated ζ1 subunit in cortex and hippocampus. In addition, PSD-95 and α-actinin-2, proteins essential for anchoring NMDA receptors, were decreased. Finally, we found a decreased level of tyrosine-phosphorylated ε1 subunit, another determinant of NMDA receptor trafficking, in R6/2 hippocampus. Taken together, these data demonstrate multiple levels of NMDA receptor dysregulation, including abnormalities in mRNA expression levels, receptor stoichiometry, protein phosphorylation, and receptor trafficking.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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