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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 2

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Tests of dysbindin-1 antibody specificity in COS-7 cells. Such cells nor...
Tests of dysbindin-1 antibody specificity in COS-7 cells. Such cells normally express no detectable dysbindin. (A) The antibody PA3111Ae2 (1:100) recognizes dysbindin-1 only in COS-7 cells transfected with dysbindin-1 expression constructs. It does not recognize antigens in COS-7 cells transfected with dysbindin-2 expression constructs. (B) The antibody M10RP-FLA (1:50) recognizes dysbindin-2, which is of lower molecular weight than dysbindin-1. (C) Equal loading of samples was demonstrated with β-tubulin antibody T4026 from Sigma-Aldrich (1:5,000).

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