Role of dysbindin in dopamine receptor trafficking and cortical GABA function

Yuanyuan Ji, Feng Yang, Francesco Papaleo, Huai Xing Wang, Wen Jun Gao, Daniel R. Weinberger, Bai Lu

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)19593-19598
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number46
DOIs
StatePublished - Nov 17 2009
Externally publishedYes

Keywords

  • Dopamine D2 receptor
  • Prefrontal cortex
  • Schizophrenia

ASJC Scopus subject areas

  • General

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