Regulation of striatal dopamine responsiveness by Notch/RBP-J signaling

M. Toritsuka, S. Kimoto, K. Muraki, M. Kitagawa, T. Kishimoto, A. Sawa, K. Tanigaki

Research output: Contribution to journalArticlepeer-review

Abstract

Dopamine signaling is essential for reward learning and fear-related learning, and thought to be involved in neuropsychiatric diseases. However, the molecular mechanisms underlying the regulation of dopamine responsiveness is unclear. Here we show the critical roles of Notch/RBP-J signaling in the regulation of dopamine responsiveness in the striatum. Notch/RBP-J signaling regulates various neural cell fate specification, and neuronal functions in the adult central nervous system. Conditional deletion of RBP-J specifically in neuronal cells causes enhanced response to apomorphine, a non-selective dopamine agonist, and SKF38393, a D1 agonist, and impaired dopamine-dependent instrumental avoidance learning, which is corrected by SCH23390, a D1 antagonist. RBP-J deficiency drastically reduced dopamine release in the striatum and caused a subtle decrease in the number of dopaminergic neurons. Lentivirus-mediated gene transfer experiments showed that RBP-J deficiency in the striatum was sufficient for these deficits. These findings demonstrated that Notch/RBP-J signaling regulates dopamine responsiveness in the striatum, which may explain the mechanism whereby Notch/RBP-J signaling affects an individual's susceptibility to neuropsychiatric disease.

Original languageEnglish (US)
Article numbere1049
JournalTranslational psychiatry
Volume7
Issue number3
DOIs
StatePublished - Mar 7 2017

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry

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