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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 7

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Quantification of dysbindin-1 reductions in extrasomatic (i.e., neuropil...
Quantification of dysbindin-1 reductions in extrasomatic (i.e., neuropil) areas of the subiculum and hippocampus proper in schizophrenia compared to matched control cases in the University of Pennsylvania cohort. Data were collected only from neuropil known to contain terminals of glutamatergic pathways arising in the hippocampus. CA2/3 (o) and CA2/3 (r) respectively designate stratum oriens and stratum radiatum of CA2 and CA3. Relative OD was used to quantify dysbindin-1 immunoreactivity. Each data point in these bivariate graphs give the OD of dysbindin-1 immunoreactivity in a schizophrenia case (y axis) versus that in its matched control (x axis). Note that 73_93% of the data points lie below the diagonal lines, indicating that neuropil dysbindin-1 in all four brain areas was lower in the vast majority of the schizophrenia cases compared to matched controls.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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