The NR1 subunit of the glutamate/NMDA receptor in the superior temporal cortex in schizophrenia and affective disorders

The NMDA receptor has been implicated in the pathophysiology of several diseases including schizophrenia and affective disorders. We have investigated the NR1 subunit of the NMDA receptor in a well-defined series of psychiatric cases using radioligand binding and quantitative immunoblotting techniques. Saturable radioligand binding of [(3)H]L-689,560 to the glycine site on this subunit of the NMDA receptor was undertaken in superior temporal cortex of patients with schizophrenia, bipolar disorder, depression and matched control subjects. A tendency towards an increased receptor density was found in schizophrenia. A significant decrease in NMDA receptor density below control value was found in both bipolar and depressive disorders. The immunoblotting technique was used to identify NR1 protein in the same series of cases of which two bands were identified consistent with NR1 splice variants. A tendency to a decrease in the density of the NR1 upper band below control values was found in bipolar and depressed patients, but not schizophrenics. Consistent with this observation, the ratio between the upper and lower NR1-immunoreactive bands showed a significant decrease in bipolar disorder, although the ratio in depression did not reach significance. No significant difference was found in the NR1 lower band in any patient group compared with control. The finding of an increase NMDA receptor density in schizophrenia is consistent with the previous reports, with a possible compensatory response to glutamatergic deficits in superior temporal cortex in schizophrenia. The findings in affective disorders are interesting in respect of reports of cortical NMDA receptor deficits in suicide victims, although antidepressant drug treatment may contribute to these changes.

[1]  M. Bennett,et al.  Alternatively spliced isoforms of the NMDARI receptor subunit , 1995, Trends in Neurosciences.

[2]  S. Hirsch,et al.  NMDA receptor mRNA correlation with antemortem cognitive impairment in schizophrenia. , 1996, Neuroreport.

[3]  D. Javitt,et al.  The role of N-Methyl-D-Aspartate (NMDA) receptor-mediated neurotransmission in the pathophysiology and therapeutics of psychiatric syndromes , 1998, European Neuropsychopharmacology.

[4]  R. Yolken,et al.  The Stanley Foundation brain collection and Neuropathology Consortium , 2000, Schizophrenia Research.

[5]  M. Toru,et al.  Increases in strychnine-insensiive glycine binding sites in cerebral cortex of chronic schizophrenics: Evidence for glutamate hypothesis , 1994, Biological Psychiatry.

[6]  J. Meador-Woodruff,et al.  Glutamate receptor expression in schizophrenic brain , 2000, Brain Research Reviews.

[7]  K. Davis,et al.  Expression of the ionotropic glutamate receptor subunits and NMDA receptor-associated intracellular proteins in the substantia nigra in schizophrenia. , 2004, Brain research. Molecular brain research.

[8]  J. Deakin,et al.  NR2B-containing NMDA receptors are up-regulated in temporal cortex in schizophrenia. , 1999, Neuroreport.

[9]  S. Potkin,et al.  Selective alterations in gene expression for NMDA receptor subunits in prefrontal cortex of schizophrenics , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[10]  D J Healy,et al.  Ionotropic glutamate receptor binding and subunit mRNA expression in thalamic nuclei in schizophrenia. , 2000, The American journal of psychiatry.

[11]  R. Huganir,et al.  Inactivation of NMDA Receptors by Direct Interaction of Calmodulin with the NR1 Subunit , 1996, Cell.

[12]  J. Deakin,et al.  Asymmetrical reductions of hippocampal NMDAR1 glutamate receptor mRNA in the psychoses , 2001, Neuroreport.

[13]  A. Mackinnon,et al.  Decreased hippocampal NMDA, but not kainate or AMPA receptors in bipolar disorder. , 2003, Bipolar disorders.

[14]  D. Braus,et al.  Effects of Long-Term Antipsychotic Treatment on NMDA Receptor Binding and Gene Expression of Subunits , 2003, Neurochemical Research.

[15]  R. Conley,et al.  Ionotropic glutamate receptors and expression of N-methyl-D-aspartate receptor subunits in subregions of human hippocampus: effects of schizophrenia. , 2000, The American journal of psychiatry.

[16]  P. Skolnick,et al.  Adaptation of the N-methyl-D-aspartate receptor complex following chronic antidepressant treatments. , 1994, The Journal of pharmacology and experimental therapeutics.

[17]  G. Reynolds,et al.  Increased density of glutamate/N-methyl-d-aspartate receptors in putamen from schizophrenic patients , 1998, Neuroscience Letters.

[18]  D. Javitt,et al.  Recent advances in the phencyclidine model of schizophrenia. , 1991, The American journal of psychiatry.

[19]  Deborah Yurgelun-Todd,et al.  Progressive ventricular enlargement in schizophrenia: Comparison to bipolar affective disorder and correlation with clinical course , 1990, Biological Psychiatry.

[20]  G. Nowak,et al.  Alterations in the N-methyl-d-asparatate (NMDA) receptor complex in the frontal cortex of suicide victims , 1995, Brain Research.

[21]  G. Reynolds,et al.  Increased density of glutamate/N-methyl-d-aspartate receptors in superior temporal cortex in schizophrenia , 2001, Neuroscience Letters.

[22]  O. H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.

[23]  G. Reynolds,et al.  Deficit of [3H]L-689,560 binding to the glycine site of the glutamate/NMDA receptor in the brain in Huntington's disease , 1994, Journal of the Neurological Sciences.

[24]  S. Catts,et al.  Increased levels of expression of an NMDAR1 splice variant in the superior temporal gyrus in schizophrenia , 2000, Neuroreport.

[25]  C. Beasley,et al.  Neurochemical correlates of cortical GABAergic deficits in schizophrenia: selective losses of calcium binding protein immunoreactivity , 2001, Brain Research Bulletin.