¹Department of Psychiatry (Center for Neurobiology and Behavior), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
²Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
³Department of Neuroscience and
⁴Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

Address correspondence to: Steven E. Arnold, Center for Neurobiology and Behavior, 547B Clinical Research Building, University of Pennsylvania, 415 Curie Boulevard, Philadelphia, Pennsylvania 19104-6140, USA. Phone: (215) 573-2840; Fax: (215) 573-6382; E-mail: sarnold@mail.med.upenn.edu .

Received for publication October 29, 2003, and accepted in revised form February 3, 2004.

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., ß-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.