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

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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Summary of results in the context of information flow in the HF. Dysbind...
Summary of results in the context of information flow in the HF. Dysbindin-1 in the HF (A) was found in neurons that supply intrinsic glutamatergic connections in that structure. As diagrammed in B, dysbindin-1 neurons in DGh (red dots) innervate DGiml (red band); those in CA2 and CA3 (green dots) innervate much of CA1_3 (green field); and those in CA1 (yellow dots) innervate the subiculum (yellow field) and entorhinal cortex (ERC). Those intrinsic glutamatergic pathways are part of a broader series of HFl circuits diagrammed in C. The blue star-bursts there indicate the loci of dysbindin-1 reductions found in schizophrenia, which potentially disrupt normal glutamatergic transmission in the DG, hippocampus proper, and subiculum. See Discussion for consideration of the possible consequences for information flow in the HF. D, dendrites; DGoml, outer molecular layer of the DG; G, dentate granule cell; H, dentate hilar cell; mf, mossy fiber; pp, perforant path; r/o, strata radiatum and oriens; sc, Schaffer collateral. Scale bars in A and B: 2 mm.