title: Increased expression of dysbindin-1A leads to a selective deficit in NMDA receptor signaling in the hippocampus.
abstract: The effects of the major schizophrenia susceptibility gene disease DTNBP1 on disease risk are likely to be mediated through changes in expression level of the gene product, dysbindin-1. How such changes might influence pathogenesis is, however, unclear. One possible mechanism is suggested by recent work establishing a link between altered dysbindin-1 expression and changes in surface levels of N-methyl-d-aspartate receptors (NMDAR), although neither the precise nature of this relationship, nor the mechanism underlying it, are understood. Using organotypic slices of rat hippocampus, we show that increased expression of dysbindin-1A in pyramidal neurons causes a severe and selective hypofunction of NMDARs and blocks induction of LTP. Cell surface, but not cytoplasmic, expression of the NR1 subunit of the NMDAR is decreased, suggesting dysregulation of NMDAR trafficking and, consistent with this, pharmacological inhibition of clathrin-dependent endocytosis is sufficient to reverse the deficit in NMDAR signaling. These results support the idea that the level of the NMDAR at the plasma membrane is modulated by changes in dysbindin-1 expression and offer further insight into the role of dysbindin-1 at an important cellular pathway implicated in schizophrenia.
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Jeans
authors.forename: Richard
authors.initials: R
authors.lastname: Malins
authors.forename: Zahid
authors.initials: Z
authors.lastname: Padamsey
authors.forename: Marcia
authors.initials: M
authors.lastname: Reinhart
authors.forename: Nigel
authors.initials: N
authors.lastname: Emptage
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D001703:Biophysics; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D002966:Clathrin / Q000494:pharmacology; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D004558:Electric Stimulation; D004622:Embryo, Mammalian; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014162:Transfection / Q000379:methods; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D002966:Clathrin; C574928:Dtnbp1 protein, rat; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D018690:Excitatory Amino Acid Agonists; D008164:Luminescent Proteins; C409466:NR1 NMDA receptor; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D026941:Sodium Channel Blockers; C054562:yellow fluorescent protein, Bacteria; D013779:Tetrodotoxin; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C104722:glutamate receptor ionotropic, AMPA 2