Striatal ionotropic glutamate receptor expression in schizophrenia, bipolar disorder, and major depressive disorder
Introduction
A growing body of evidence has implicated glutamatergic abnormalities in major psychiatric conditions, particularly schizophrenia. Glutamate exerts its effects as a neurotransmitter through four distinct receptor families (Fig. 1). The ionotropic receptors constitute three of the four families, and exist as N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA), and kainate subtypes. Each of the ionotropic receptors is composed of multimeric associations of subunits that form ligand-gated ion channels. On the other hand, the metabotropic glutamate receptors are seven transmembrane domain, G-protein coupled receptors [23].
The ionotropic receptors are composed of family-specific subunits [23]. The AMPA receptor subunits are derived from four different genes, gluR1-gluR4. Kainate receptors are composed of subunits derived from genes for the low affinity gluR5-gluR7 and high affinity KA1-KA2 subunits. Subunits associated with both the AMPA and kainate receptors exist in multiple forms due to alternative splicing and editing of their respective transcripts [23]. Accordingly, there is the potential for heterogeneity in both AMPA and kainate receptors, based on subunit composition and transcriptional modification of individual subunits. Subunit composition is physiologically relevant for both AMPA and kainate receptors, as unique pharmacological properties are associated with specific subunit complements in the final receptors. For example, gluR2-containing AMPA receptors have decreased calcium ion flux, which decreases the electrophysiological activity of these receptors 5, 15, 22, 29, 56.
The NMDA receptor subunits are encoded by five genes, NR1 and NR2A-NR2D [23]. NR1 can be expressed as one of eight isoforms, due to the alternative splicing of exons 5, 21, and 22 9, 23, 42. The pharmacological regulation of the NMDA receptor depends on the unique combination of binding sites [23]. There is a primary site for the binding of glutamate. A separate glycine binding site must also be occupied before glutamate can activate the ion channel. Modulatory binding sites for polyamines, pH, and zinc have also been identified. There is a site for magnesium, which blocks the channel at physiological concentrations. This blockade is voltage dependent; partial depolarization of the cell membrane will extrude magnesium. Therefore, presynaptic glutamate release and postsynaptic pre-depolarization are both required for NMDA receptor activity. Finally, there is a site within the ion channel itself associated with the binding of uncompetitive antagonists of the NMDA receptor, such as PCP, ketamine, and MK-801. These antagonists are use-dependent, i.e., the ion channel must be opened for these compounds to bind to the receptor, so there must be cooperativity between multiple sites for occupancy of uncompetitive antagonists. Similar to the AMPA and kainate receptors, subunit composition is physiologically relevant: the NMDA binding sites are associated with different subunits, and their affinities can vary depending on subunit composition 3, 14, 18, 35, 41, 50.
Several lines of evidence have implicated glutamatergic dysfunction in schizophrenia, particularly associated with the NMDA receptor. For example, uncompetitive inhibitors of the MK-801 sensitive intrachannel site can cause psychosis in non-psychiatrically ill individuals 33, 37, and worsen psychotic symptoms in persons with schizophrenia 27, 34, 36. Agonists of the glycine co-agonist site of the NMDA receptor have been found to ameliorate negative psychotic symptoms in schizophrenia 7, 16, 21, 28, 51. These observations suggest that schizophrenia may be associated with decreased NMDA receptor activity 6, 27. Although the NMDA receptor is the subtype of glutamate receptor usually implicated in schizophrenia, the other ionotropic glutamate receptors also may be abnormal in this illness. A growing literature suggests abnormal expression of all three families of ionotropic glutamate receptors in the brain in schizophrenia [39], although in complex and regionally specific patterns. While prefrontal and cingulate cortex, and medial temporal lobe structures have been most often studied in psychiatric illnesses, these receptors are expressed in other brain regions associated with the limbic circuitry felt to be disturbed in psychiatric illnesses, including the striatum and thalamus.
In the present study, we have examined the expression of the NMDA, AMPA, and kainate receptors in the striatum in persons with schizophrenia, as well as bipolar disorder, major depression, and a comparison group. We have approached this study by examining the expression of these receptors at different levels of gene expression, by determining the expression of the transcripts encoding each of the subunits, as well as multiple binding sites associated with these receptors. This is the first comprehensive study of the expression of the ionotropic glutamate receptors in the striatum in these psychiatric disorders, and adds to the growing literature that suggests heterogeneity of abnormal expression of these receptors in the brain in schizophrenia and other psychiatric illnesses.
Section snippets
Subjects
Sixty subjects from the Stanley Foundation Neuropathology Consortium were studied, comprised of four groups of 15 subjects each with diagnoses of schizophrenia, bipolar disorder, major depressive disorder, and a comparison group. A detailed description of this collection has been published recently [57]; summary characteristics of the subjects are shown in Table 1. Cryostat-sectioned (14 um) slides from the fresh frozen half of these brains were provided to us by the Stanley Foundation
NMDA receptor expression
The transcripts encoding the ionotropic glutamate receptor subunits and multiple binding sites were readily identifiable in the striatal subregions studied (Fig. 2). All five of the NMDA subunits were detected, although NR1, NR2A, and NR2B were by far the most abundant. The four ligands used to label the specific binding sites associated with the NMDA complex were also visualized throughout the striatum. There were few significant differences in the expression of the molecules that are
Discussion
Past studies on the expression of the ionotropic glutamate receptors in the brain in psychiatric illnesses have almost exclusively focused on schizophrenia, have concentrated on cortical and medial temporal lobe structures, and have generally revealed complex, region- and receptor-specific abnormalities. Relatively few studies have focused on the expression of these receptors in subcortical limbic structures. Our results reveal that there are no differences in the expression of the ionotropic
Acknowledgements
This work was supported by MH53327 to Dr. Meador-Woodruff. Postmortem brains were donated by the Stanley Foundation Brain Consortium courtesy of Drs. Llewellyn B. Bigelow, Juraj Cervenak, Mary M. Herman, Thomas M. Hyde, Joel E. Kleinman, Jose D. Paltan, Robert M. Post, E. Fuller Torrey, Maree J. Webster, and Robert H. Yolken.
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