Decreased NR1, NR2A, and SAP102 transcript expression in the hippocampus in bipolar disorder

Robert E McCullumsmith, Lars V Kristiansen, Monica Beneyto, Elizabeth Scarr, Brian Dean, James H Meador-Woodruff, Robert E McCullumsmith, Lars V Kristiansen, Monica Beneyto, Elizabeth Scarr, Brian Dean, James H Meador-Woodruff

Abstract

Objectives: Schizophrenia is associated with dysfunction of glutamatergic neurotransmission, and several studies have suggested glutamatergic abnormalities in bipolar disorder. Recent data suggest involvement of the NMDA receptor signaling complex, which includes NMDA receptor subunits as well as associated intracellular interacting proteins critical for NMDA receptor assembly, trafficking, and activation; the most well-characterized being PSD93, PSD95, SAP102, and NF-L. Previously, studies from our laboratories have described changes in glutamate receptor subunit transcript and binding site expression in schizophrenia and changes in NMDA receptor binding site expression in bipolar disorder in postmortem brain tissue. In the present work, we focus on the expression of these molecules in hippocampus in schizophrenia and bipolar affective disorder I.

Methods: 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 affective disorder I, and a comparison group. We also measured [(3)H]CGP39653 and [(3)H]MK-801 binding site expression in the hippocampus in schizophrenia.

Results: There was a significant decrease in the expression of transcripts for NR1 and NR2A subunits and SAP102 in bipolar disorder. We did not detect any changes in these transcripts or in binding site expression in the hippocampus in schizophrenia.

Conclusions: We propose that the NMDA receptor signaling complex, including the intracellular machinery that is coupled to the NMDA receptor subunits, is abnormal in the hippocampus in bipolar disorder. These data suggest that bipolar disorder might be associated with abnormalities of glutamate-linked intracellular signaling and trafficking processes.

Figures

Figure 1
Figure 1
In situ hybridization using [35S] labeled antisense riboprobes for NMDA receptor subunit transcripts in the hippocampal subfields CA1, CA2, CA3, and CA4, the dentate gyrus (DG), and the subiculum (Sub).
Figure 2
Figure 2
In situ hybridization using [35S] labeled antisense riboprobes for neurofilament light (NF-L) (A), postsynaptic density protein 93 (PSD93) (B), PSD95 (C), and synapse associated protein 102 (SAP102) (D) in hippocampal subfields, the dentate gyrus, and the subiculum.
Figure 3
Figure 3
Expression of NMDA receptor subunit transcripts in hippocampal regions CA1, CA2, CA3, CA4, dentate gyrus (DG) and subiculum (Sub) from patients with bipolar disorder (BD), schizophrenia and a control group (CTL). Data expressed as fmol mRNA/g tissue (mean ± SEM).
Figure 4
Figure 4
Expression of transcripts for NMDA receptor interacting molecules in hippocampal regions CA1, CA2, CA3, CA4, dentate gyrus (DG) and subiculum (Sub) from patients with bipolar disorder (BD), schizophrenia and a control group (CTL). Data expressed as fmol mRNA/g tissue (mean ± SEM).
Figure 5
Figure 5
[3H]MK-801 (A) and [3H]CGP39653 (B) binding site expression in hippocampal regions CA1, CA2, CA3, dentate gyrus (DG) and subiculum (Sub). Panel A’ is [3H]MK-801 binding in the presence of unlabeled MK-801, Panel B’ is [3H]CGP39653 binding in the presence of unlabeled L-glutamic acid.
Figure 6
Figure 6
[3H]CGP39653 and [3H]MK-801 binding site expression in hippocampal regions CA1, CA2, CA3, CA4, dentate gyrus (DG) and subiculum (Sub) from patients with schizophrenia and a control group. Data expressed as fmol/mg estimated tissue equivalent.

Source: PubMed

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