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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.

Original publication

DOI

10.1016/j.neuropharm.2011.08.007

Type

Journal article

Journal

Neuropharmacology

Publication Date

12/2011

Volume

61

Pages

1345 - 1353

Keywords

Animals, Bacterial Proteins, Biophysics, Carrier Proteins, Cells, Cultured, Clathrin, Dysbindin, Dystrophin-Associated Proteins, Electric Stimulation, Embryo, Mammalian, Endocytosis, Excitatory Amino Acid Agonists, Gene Expression Regulation, Hippocampus, Long-Term Potentiation, Luminescent Proteins, Male, Mice, N-Methylaspartate, Neurons, Organ Culture Techniques, Patch-Clamp Techniques, Protein Transport, Rats, Rats, Wistar, Receptors, AMPA, Receptors, N-Methyl-D-Aspartate, Signal Transduction, Sodium Channel Blockers, Tetrodotoxin, Transfection, alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid