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

Talbot, Konrad, Eidem, Wess L., Tinsley, Caroline L., Benson, Matthew A., Thompson, Edward W., Smith, Rachel J., Hahn, Chang-Gyu, Siegel, Steven J., Trojanowski, John Q., Gur, Raquel E., Blake, Derek and Arnold, Steven E. 2004. Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. The Journal of Clinical Investigation 113 (9) , pp. 1353-1363. 10.1172/JCI200420425

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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., beta-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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: American Society for Clinical Investigation
ISSN: 0021-9738
Last Modified: 04 Jun 2017 08:38
URI: http://orca-mwe.cf.ac.uk/id/eprint/81680

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