Several lines of evidence suggest abnormal expression of ionotropic glutamate receptors in schizophrenia.  Recently, converging studies have indicated that disturbances in glutamatergic neurotransmission may also play a role in the pathophysiology of other psychiatric illnesses.  Although alterations of expression of ionotropic glutamate receptor subunits have been reported in limbic cortex and medial temporal lobe structures in schizophrenia, possible changes in the expression of these receptors in mood disorders have not been well investigated.  In the present study, we have determined NMDA, AMPA, and kainate receptor subunit expression in the dorsolateral prefrontal (DLPFC) and anterior cingulate (ACC) cortex of brains from subjects with schizophrenia, bipolar disorder, major depression and a comparison group, by using both in situ hybridization for subunit transcript expression and receptor autoradiography.  We found differences between the alterations that occur in the DLPFC versus ACC.  In schizophrenia the most dramatic changes in glutamate receptor expression occur in the DLPFC, where all the NMDA subunits, except for NR2D, all AMPA subunits, except for GluR1, and GluR5,7 and KA2 among the kainate subunits, are decreased.  Interestingly NR2D is increased, while GluR1, GluR6 and KA1 are not changed in the illness.  In the ACC in schizophrenia only NMDA subunit NR2A, and kainate subunits GluR5 and GluR7 are decreased, while AMPA subunits GluR3 and GluR4 are increased.  In depression and bipolar disorder the alterations are also more numerous in the DLPFC, with some similarities between both cortical areas, with decreased expression of NR1, NR2A in both depression and bipolar disorder and decreased GluR7 expression in bipolar disorder.  The differences in bipolar disorder between the two cortical areas were a decrease in NR2C expression and an increase in GluR6 transcript in ACC but not DLPFC, and a decrease in GluR2, GluR7, and KA2 in DLPFC but not ACC.  In the depressive group there is an increased expression of GluR4 only in ACC and of GluR5 only in DLPFC.  The expression of GluR2 and GluR3 was decreased only in the prefrontal cortex.  From these results we suggest a higher level of alterations in the DLPFC in schizophrenia and the mood disorders, but even more so in schizophrenia, where we found a decrease of almost all the ionotropic receptor subunits.

Monica Beneyto