Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia.
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.
Talbot
Konrad
K
Department of Psychiatry (Center for Neurobiology and Behavior), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6140, USA.
Eidem
Wess L
WL
Tinsley
Caroline L
CL
Benson
Matthew A
MA
Thompson
Edward W
EW
Smith
Rachel J
RJ
Hahn
Chang-Gyu
CG
Siegel
Steven J
SJ
Trojanowski
John Q
JQ
Gur
Raquel E
RE
Blake
Derek J
DJ
Arnold
Steven E
SE
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002522:Chlorocebus aethiops; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010414:Pennsylvania; D017729:Presynaptic Terminals / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics / Q000473:pathology*; D012744:Sex Ratio
D002352:Carrier Proteins; C432416:DTNBP1 protein, human; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D017470:Receptors, Glutamate