Increased expression of dysbindin-1A leads to a selective deficit in NMDA receptor signaling in the hippocampus

Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
Neuropharmacology (Impact Factor: 5.11). 08/2011; 61(8):1345-53. DOI: 10.1016/j.neuropharm.2011.08.007
Source: PubMed


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.

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    • "Author's personal copy role of dysbindin-1 in modulating both DAergic and glutamatergic signaling systems, for the purpose of this chapter we will specifically focus on the implication of dysbindin-1 for the DAergic system. The discussion of the effects of dysbindin-1 on the glutamatergic system can be found elsewhere (Dickman and Davis, 2009; Ghiani and Dell'Angelica, 2011; Jeans et al., 2011; Karlsgodt et al., 2011; Papaleo and Weinberger, 2011; Saggu et al., 2013; Tang et al., 2009b; Wirth et al., 2012). "
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