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

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.

ASCL1-regulated DARPP-32 and t-DARPP stimulate small cell lung cancer growth and neuroendocrine tumour cell proliferation

“…However, Notch/RBP-J signalling plays a key role in the regulation of dopamine responsive as neuron-specific loss of Notch/RBP-J signalling has been shown to cause a deficit in dopamine-dependent instrumental avoidance learning and hyper-responsiveness to apomorphine and SKF38393, a D1 agonist. 75 Brain-derived neurotrophic factor (BDNF) transcriptionally regulates DARPP-32 expression in neurons, as exemplified by delayed and decreased neuronal DARPP-32 expression in BDNF knockout mice, a phenotype that could be rescued ex vivo through the addition of BDNF to cultured neurons derived from BDNF null mice. 76 BDNF and ASCL1 were dysregulated and accompanied by aberrant expression of DARPP-32, one of their common transcriptional targets, in striatal neural stem cells derived from a hypoxanthine-guanine phosphoribosyltransferase (HPRT) knockout mouse model of Lesch-Nyhan Syndrome, a neurodevelopmental disorder caused by mutations in the gene encoding HPRT.…”

H3.3 Barcoding of Nucleus Accumbens Transcriptional Activity Identifies Novel Molecular Cascades Associated with Cocaine Self-administration in Mice

“…The third transcription factor identified, Rbpj1, is a member of a family of molecules that are an integral part of Notch signaling, which regulates cell differentiation, cell fate, and neural progenitor selfrenewal (Roese-Koerner et al, 2017). Interestingly, Rbpj1 also regulates dopamine responsiveness in the striatum and may be a predictor of vulnerability to psychiatric disease (Toritsuka et al, 2017). Overall, the ontology and binding motif analyses identified established and novel pathways in neurons that are associated with volitional cocaine consumption.…”

Alcohol Activates Scabrous-Notch to Influence Associated Memories

“…A recent mouse study has intriguingly identified a link between Notch/RBP-J and striatal dopamine function (Toritsuka et al, 2017). Conditional knockout of RBP-J (Su(H) in flies) in neurons decreased striatal dopamine release, increased D1 agonist responsivity, and affected the acquisition and maintenance of conditioned avoidance behavior (Toritsuka et al, 2017). Since D1 and D2 receptor binding and expression were not altered in the absence of RBP-J , the cellular mechanisms of how Notch/RBP-J signaling affects dopaminergic activity still remain unclear.…”