Research ReportDecreased NR1, NR2A, and SAP102 transcript expression in the hippocampus in bipolar disorder
Introduction
The glutamate hypothesis of schizophrenia was originally based on the observation that phencyclidine (PCP) can precipitate a schizophreniform psychosis that is indistinguishable from schizophrenia in non-psychiatrically ill persons. Since PCP is an antagonist of the NMDA subtype of the glutamate receptor, it has been postulated that NMDA receptor dysfunction contributes to psychotic pathophysiology. Postmortem studies of persons afflicted with schizophrenia and, to a lesser extent bipolar disorder, have demonstrated region- and subunit-specific alterations in the expression of NMDA receptor subunit transcripts and binding sites, supporting a hypothesis of NMDA receptor dysfunction in these illnesses (Akbarian et al., 1996, Clinton et al., 2003, Dean et al., 1999, Ibrahim et al., 2000b, Law and Deakin, 2001, Thompson et al., 2003).
The NMDA receptor is a ligand-gated ion channel formed by an obligate NR1 subunit and combinations of NR2A–D subunits (Hollmann and Heinemann, 1994). The NMDA receptor subunits have consensus phosphorylation and protein–protein interaction sites that link the NMDA receptor with intracellular signaling pathways. The development of techniques such as yeast 2-hybrid that permit identification of previously unknown protein–protein interactions has led to the discovery of NMDA receptor-interacting proteins that modulate receptor activity via interactions with the cytoplasmic tails of the NMDA subunits. These protein–protein interactions facilitate clustering and anchoring of the NMDA receptor in the postsynaptic density, leading to the assembly of a signaling complex that involves the receptor, cytostructural proteins, and signal transduction enzymes (McCullumsmith et al., 2004, Meador-Woodruff et al., 2003). The NMDA receptor-interacting proteins are enriched in the postsynaptic density (PSD) and include PSD95, PSD93, and synapse-associated protein 102 (SAP102), which primarily interact with the NR2B subunit and neurofilament-light (NF-L), which interacts with exon 21 containing NR1 subunits (Meador-Woodruff et al., 2003, Sans et al., 2003).
Expression of NMDA receptors and NMDA receptor-interacting proteins parallels the widespread distribution of glutamatergic synapses throughout the brain. In medial temporal lobe structures, the expression of these molecules is consistent with well-characterized glutamatergic circuitry. This region includes the dentate gyrus, the hippocampal subfields, and the subiculum and adjacent cortical regions that are reciprocally interconnected via glutamatergic projections (Douglas et al., 1990). Previously, changes in the structure and function of the medial temporal lobe in schizophrenia, and to a lesser extent bipolar disorder, have been reported based upon techniques utilizing imaging, histopathology, and measures of gene expression (Csernansky et al., 2002, Harrison and Eastwood, 2001, Medoff et al., 2001, Seidman et al., 2002, Takamori et al., 2000). Abnormalities of NMDA receptor expression have been reported in the hippocampus in schizophrenia and bipolar disorder, consistent with the hypothesis of altered glutamate neurotransmission in these illnesses (Dean et al., 1999, Scarr et al., 2003). The preponderance of data implicating the hippocampus and related structures in schizophrenia and bipolar disorder, taken together with the robust demonstration of glutamate receptor dysfunction, suggests that alterations of glutamatergic neurotransmission, and in particular the NMDA receptor signaling complex, likely underlie some of these hippocampal abnormalities. Thus, we performed in situ hybridization to assess hippocampal expression of the transcripts encoding NMDA receptor subunits NR1, 2A, 2B, 2C and 2D, and the transcripts for the NMDA receptor associated PSD proteins PSD95, PSD93, NF-L, and SAP102 in subjects with schizophrenia, bipolar disorder, and a comparison group. We also measured NMDA receptor binding site expression in the hippocampus in schizophrenia.
Section snippets
Results
Sense and antisense probes were prepared for NR1, NR2A, NR2B, NR2C, NR2D, PSD95, PSD93, SAP102, and NF-L. Specific labeling was only observed for sections incubated with antisense riboprobe. We detected NR1, NR2A, NR2B, NR2C, NR2D, PSD95, PSD93, SAP102, and NF-L transcript expression in the hippocampal subfields CA1, CA2, CA3, and CA4, the dentate gyrus (DG), and the subiculum (Sub) (Fig. 1, Fig. 2).
In the hippocampal subfields, DG, and Sub, we detected an association between NR1, NR2A, and
Discussion
We found significant decreases in NR1 and NR2A transcript expression in the hippocampus in bipolar disorder (Fig. 3). These findings are consistent with a previous report of decreased [3H]CGP39653 and [3H]MK-801 binding site expression in bipolar disorder in the same subjects. [3H]CGP39653 binds to the glycine coagonist site which is on the NR1 subunit, while [3H]MK-801 binds to a site accessible only when the ion channel is open and preferentially binds NR2A- or NR2B-containing receptor
Conclusions
Our findings of decreased expression of NMDA receptor subunits and an NMDA receptor-interacting protein in the hippocampus in bipolar disorder suggest that NMDA receptor activity may be abnormal in this illness. Decreases in NMDA receptor subunit and binding site expression suggest that the overall level of NMDA receptor expression may be decreased in bipolar disorder. The decrease in SAP102 mRNA expression suggests that there may be a deficit in NMDA receptor trafficking. Our data suggest that
Subjects
Twenty-four subjects from the neural tissue repository at the Rebecca L. Cooper Research Laboratories, Victoria, Australia, were studied, comprised of three groups of 8 subjects each with diagnoses of schizophrenia, bipolar disorder, and normal controls. The left hippocampi from each subject were obtained as previously described (Dean et al., 2003, Thomas et al., 2003). Blocks of hippocampal tissue at 22 mm rostral to the anterior commissure were taken using a standard methodology (Scarr et
Acknowledgments
This work was supported by a Pfizer Postdoctoral Fellowship (REM) and MH53327 (JMW), Stanley Research Centre Grant 03-RC-002 (BD), and in part by a project grant from the National Health and Medical Research Council of Australia #14253 (BD). The authors would like to thank Geoff Pavey for technical assistance and as curator of the brain bank and Robyn Bradbury for technical assistance.
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