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.
Highlights
Dopamine (DA) signaling is highly related to reward-related learning, which contributes to fear-related learning.[1,2]Abnormalities in DA neurotransmission are thought to exist in neuropsychiatric diseases
We show the critical roles of Notch/RBP-J signaling in the regulation of dopamine responsiveness in the striatum
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
Summary
Dopamine (DA) signaling is highly related to reward-related learning, which contributes to fear-related learning.[1,2]Abnormalities in DA neurotransmission are thought to exist in neuropsychiatric diseases. Dopamine (DA) signaling is highly related to reward-related learning, which contributes to fear-related learning.[1,2]. Notch[4] has been reported to be associated with schizophrenia.[3,4,5] it remains unknown whether deficits in Notch/RBP-J signaling are involved in schizophrenia-like behavioral abnormalities or not. Notch/RBP-J signaling is highly conserved and known to play pivotal roles in various aspects of developmental neural cell fate specification,[6,7,8,9,10] dendrite morphogenesis[11,12,13] and neuronal functions in the adult central nervous system.[14,15,16,17,18] Notch/RBP-J signaling regulates synaptic plasticity and memory formation in both invertebrates and vertebrates.[14,15,16,17,18,19] In the absence of Notch activation, RBP-J functions as a transcriptional repressor.[9,20] Interaction of the
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