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Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia
Konrad Talbot, … , Derek J. Blake, Steven E. Arnold
Konrad Talbot, … , Derek J. Blake, Steven E. Arnold
Published May 1, 2004
Citation Information: J Clin Invest. 2004;113(9):1353-1363. https://doi.org/10.1172/JCI20425.
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Article Neuroscience

Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia

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Abstract

Eleven studies now report significant associations between schizophrenia and certain haplotypes of single-nucleotide polymorphisms in the gene encoding dysbindin-1 at 6p22.3. Dysbindin-1 is best known as dystrobrevin-binding protein 1 (DTNBP1) and may thus be associated with the dystrophin glycoprotein complex found at certain postsynaptic sites in the brain. Contrary to expectations, however, we found that when compared to matched, nonpsychiatric controls, 73–93% of cases in two schizophrenia populations displayed presynaptic dysbindin-1 reductions averaging 18–42% (P = 0.027–0.0001) at hippocampal formation sites lacking neuronal dystrobrevin (i.e., β-dystrobrevin). The reductions, which were not observed in the anterior cingulate of the same schizophrenia cases, occurred specifically in terminal fields of intrinsic, glutamatergic afferents of the subiculum, the hippocampus proper, and especially the inner molecular layer of the dentate gyrus (DGiml). An inversely correlated increase in vesicular glutamate transporter-1 (VGluT-1) occurred in DGiml of the same schizophrenia cases. Those changes occurred without evidence of axon terminal loss or neuroleptic effects on dysbindin-1 or VGluT-1. Our findings indicate that presynaptic dysbindin-1 reductions independent of the dystrophin glycoprotein complex are frequent in schizophrenia and are related to glutamatergic alterations in intrinsic hippocampal formation connections. Such changes may contribute to the cognitive deficits common in schizophrenia.

Authors

Konrad Talbot, Wess L. Eidem, Caroline L. Tinsley, Matthew A. Benson, Edward W. Thompson, Rachel J. Smith, Chang-Gyu Hahn, Steven J. Siegel, John Q. Trojanowski, Raquel E. Gur, Derek J. Blake, Steven E. Arnold

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Figure 4

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Dysbindin-1 immunohistochemistry of the human HF. (A) Diagram of the HF,...
Dysbindin-1 immunohistochemistry of the human HF. (A) Diagram of the HF, showing subdivisions and layers. The DGiml is highlighted in red to indicate a major neuropil locus of dysbindin-1. The subjacent granule cell layer is shown in green. (B) Dysbindin-1 immunoreactivity (ir) with PA3111Ae2 (1:300) in the section diagrammed in A. (C and D) Antibody specificity test showing that dysbindin-1 immunoreactivity (C) can be eliminated by preadsorption of PA3111Ae2 with 10_7 M recombinant dysbindin-1, M10FL (D). (E and F) Dysbindin-1_positive neurons in CA3 (E) and the DGh (F). (G and H) Dysbindin-1 in the DG. The higher-magnification view in H shows dendrites of hilar neurons containing dysbindin penetrating the granule cell layer (yellow arrowheads) and extending into the molecular layer (green arrowheads). Note the dense band of presynaptic dysbindin-1 in DGiml. CA3p, stratum pyramidal of CA3; PrS, presubiculum; S, subiculum. Hippocampal layers: l, stratum lucidum; m, stratum moleculare; o, stratum oriens; p, stratum pyramidal; r, stratum radiatum. Components of the DG: g, granule cell layer; h, hilus; iml, inner molecular layer; oml, outer molecular layer. Scale bars in A and B: 2 mm; in C and D: 200 ∝m; in E_H: 50 ∝m.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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