Role of dysbindin in dopamine receptor trafficking and cortical GABA function.
Dysbindin has been implicated in the pathogenesis of schizophrenia, but little is known about how dysbindin affects neuronal function in the circuitry underlying psychosis and related behaviors. Using a dysbindin knockout line (dys(-/-)) derived from the natural dysbindin mutant Sandy mice, we have explored the role of dysbindin in dopamine signaling and neuronal function in the prefrontal cortex (PFC). Combined cell imaging and biochemical experiments revealed a robust increase in the dopamine receptor D2, but not D1, on cell surface of neurons from dys(-/-) cortex. This was due to an enhanced recycling and insertion, rather than reduced endocytosis, of D2. Disruption of dysbindin gene resulted in a marked decrease in the excitability of fast-spiking (FS) GABAergic interneurons in both PFC and striatum. Dys(-/-) mice also exhibited a decreased inhibitory input to pyramidal neurons in layer V of PFC. The increased D2 signaling in dys(-/-) FS interneurons was associated with a more pronounced increase in neuronal firing in response to D2 agonist, compared to that in wild-type interneurons. Taken together, these results suggest that dysbindin regulates PFC function by facilitating D2-mediated modulation of GABAergic function.
Ji
Yuanyuan
Y
Section on Neural Development and Plasticity, National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.
Yang
Feng
F
Papaleo
Francesco
F
Wang
Huai-Xing
HX
Gao
Wen-Jun
WJ
Weinberger
Daniel R
DR
Lu
Bai
B
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D017397:Prefrontal Cortex / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D002352:Carrier Proteins; C498992:Dtnbp1 protein, mouse; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D005680:gamma-Aminobutyric Acid