Elsevier

Brain Research

Volume 1127, 5 January 2007, Pages 108-118
Brain Research

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

https://doi.org/10.1016/j.brainres.2006.09.011Get rights and content

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 [3H]CGP39653 and [3H]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.

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.

References (50)

  • J.H. Meador-Woodruff et al.

    Distribution of D5 dopamine receptor mRNA in rat brain

    Neurosci. Lett.

    (1992)
  • M. Nankai et al.

    The pharmacology of native N-methyl-d-aspartate receptor subtypes: different receptors control the release of different striatal and spinal transmitters

    Prog. Neuro-psychopharmacol. Biol. Psychiatry

    (1998)
  • P.M. Thompson et al.

    SNAP-25 reduction in the hippocampus of patients with schizophrenia

    Prog. Neuro-psychopharmacol. Biol. Psychiatry

    (2003)
  • S. Akbarian et al.

    Selective alterations in gene expression for NMDA receptor subunits in prefrontal cortex of schizophrenics

    J. Neurosci.

    (1996)
  • M. Beneyto et al.

    Cell and laminar-specific abnormalities in AMPA and NMDA associated postsynaptic protein expression in prefrontal cortex in schizophrenia and mood disorders

    Annu. Meet. Soc. Neurosci.

    (2004)
  • S.M. Clinton et al.

    Altered transcript expression of NMDA receptor-associated postsynaptic proteins in the thalamus of subjects with schizophrenia

    Am. J. Psychiatry

    (2003)
  • J.G. Csernansky et al.

    Hippocampal deformities in schizophrenia characterized by high dimensional brain mapping

    Am. J. Psychiatry

    (2002)
  • B. Dean et al.

    Decreased hippocampal (CA3) NMDA receptors in schizophrenia

    Synapse

    (1999)
  • J.F. Dixon et al.

    The antibipolar drug valproate mimics lithium in stimulating glutamate release and inositol 1,4,5-trisphosphate accumulation in brain cortex slices but not accumulation of inositol monophosphates and bisphosphates

    Proc. Natl. Acad. Sci. U. S. A.

    (1997)
  • J.F. Dixon et al.

    Lithium acutely inhibits and chronically up-regulates and stabilizes glutamate uptake by presynaptic nerve endings in mouse cerebral cortex

    Proc. Natl. Acad. Sci. U. S. A.

    (1998)
  • R. Douglas et al.
  • A.M. Downs et al.

    An improved approach to the analysis of autoradiographs containing isolated sources of simple shape: method, theoretical basis and reference data

    J. Microsc.

    (1984)
  • X.M. Gao et al.

    Ionotropic glutamate receptors and expression of N-methyl-d-aspartate receptor subunits in subregions of human hippocampus: effects of schizophrenia

    Am. J. Psychiatry

    (2000)
  • P.J. Harrison et al.

    Neuropathological studies of synaptic connectivity in the hippocampal formation in schizophrenia

    Hippocampus

    (2001)
  • P.J. Harrison et al.

    Glutamate receptors and transporters in the hippocampus in schizophrenia

    Ann. N. Y. Acad. Sci.

    (2003)
  • Cited by (128)

    • A conceptualized model linking matrix metalloproteinase-9 to schizophrenia pathogenesis

      2020, Schizophrenia Research
      Citation Excerpt :

      Furthermore, using two-photon time-lapse imaging in combination with whole-cell patch clamp recording from CA1 hippocampal neurons, MMP-9 has been directly shown to play an instructive role in coordinating structural and physiological synaptic plasticity at glutamatergic synapses during LTP (Wang et al., 2008). Glutamate neurotransmission dysfunction, from deficits in vesicular transport in presynaptic terminals (Bitanihirwe et al., 2009; Eastwood and Harrison, 2005; Oni-Orisan et al., 2008) to altered postsynaptic expression of glutamate receptor subunits (Beneyto et al., 2007; Beneyto and Meador-Woodruff, 2008; Bitanihirwe et al., 2009; Gao et al., 2000; McCullumsmith et al., 2007; Mueller et al., 2004; Woo et al., 2008), has been implicated in the pathophysiology of schizophrenia in part by compromising synaptic plasticity and thereby leading to disruption of the functional connectional architecture of the brain (Coyle et al., 2016; Manago and Papaleo, 2017; Snyder and Gao, 2019; Uno and Coyle, 2019). Receptor trafficking represents one of the core mechanisms for the rapid changes in the density of functional glutamate receptors during synaptic plasticity (Groc and Choquet, 2006).

    View all citing articles on Scopus
    View full text