Dysbindin regulates hippocampal LTP by controlling NMDA receptor surface expression.
Abnormalities in NMDA receptor (NMDAR) function have been implicated in schizophrenia. Here, we show that dysbindin, a schizophrenia-susceptibility gene widely expressed in the forebrain, controls the surface expression of NMDARs in a subunit-specific manner. Imaging analyses revealed a marked increase in surface NR2A, but not NR2B, in hippocampal neurons derived from dysbindin-null mutant mice (Dys-/-). Exogenous expression of dysbindin reduced NR2A surface expression in both wild-type and Dys-/- neurons. Biotinylation experiments also revealed an increase in surface expression of endogenous NR2A in Dys-/- neurons. Disruption of the dysbindin gene dramatically increased NR2A-mediated synaptic currents, without affecting AMPA receptor currents, in hippocampal CA1 neurons. The Dys-/- hippocampal slices exhibited an enhanced LTP, whereas basal synaptic transmission, presynaptic properties, and LTD were normal. Thus, dysbindin controls hippocampal LTP by selective regulation of the surface expression of NR2A. These results reveal subunit-specific regulation of NMDARs by dysbindin, providing an unexpected link between these two proteins implicated in schizophrenia.
Tang
Tina Tze-Tsang
TT
Receptor Biology Section, National Institute of Neurological Disorders and Stroke, Section on Neural Development and Plasticity, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-3714, USA.
Yang
Feng
F
Chen
Bo-Shiun
BS
Lu
Yuan
Y
Ji
Yuanyuan
Y
Roche
Katherine W
KW
Lu
Bai
B
D000818:Animals; D001923:Brain Chemistry; D002352:Carrier Proteins / Q000502:physiology*; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D005786:Gene Expression Regulation / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D017774:Long-Term Potentiation; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000737:chemistry; D016194:Receptors, N-Methyl-D-Aspartate / Q000032:analysis / Q000235:genetics*; D012559:Schizophrenia / Q000209:etiology
D002352:Carrier Proteins; C498992:Dtnbp1 protein, mouse; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate