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Park, Joo Min
인지 및 사회성 연구단
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Persistently Elevated mTOR Complex 1-S6 Kinase 1 Disrupts DARPP-32–Dependent D1 Dopamine Receptor Signaling and Behaviors

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Title
Persistently Elevated mTOR Complex 1-S6 Kinase 1 Disrupts DARPP-32–Dependent D1 Dopamine Receptor Signaling and Behaviors
Author(s)
Lin, Raozhou; Learman, Lisa N.; Na, Chan-Hyun; Renuse, Santosh; Chen, Kevin T.; Chen, Po Yu; Lee, Gum-Hwa; Xiao, Bo; Resnick, Susan M.; Troncoso, Juan C.; Szumlinski, Karen K.; Linden, David J.; Joo-Min Park; Savonenko, Alena; Pandey, Akhilesh; Worley, Paul F.
Publication Date
2021-06
Journal
BIOLOGICAL PSYCHIATRY, v.89, no.11, pp.1058 - 1072
Publisher
Elsevier Inc.
Abstract
© 2020 Society of Biological PsychiatryBackground: The serine-threonine kinase mTORC1 (mammalian target of rapamycin complex 1) is essential for normal cell function but is aberrantly activated in the brain in both genetic-developmental and sporadic diseases and is associated with a spectrum of neuropsychiatric symptoms. The underlying molecular mechanisms of cognitive and neuropsychiatric symptoms remain controversial. Methods: The present study examines behaviors in transgenic models that express Rheb, the most proximal known activator of mTORC1, and profiles striatal phosphoproteomics in a model with persistently elevated mTORC1 signaling. Biochemistry, immunohistochemistry, electrophysiology, and behavior approaches are used to examine the impact of persistently elevated mTORC1 on D1 dopamine receptor (D1R) signaling. The effect of persistently elevated mTORC1 was confirmed using D1-Cre to elevate mTORC1 activity in D1R neurons. Results: We report that persistently elevated mTORC1 signaling blocks canonical D1R signaling that is dependent on DARPP-32 (dopamine- and cAMP-regulated neuronal phosphoprotein). The immediate downstream effector of mTORC1, ribosomal S6 kinase 1 (S6K1), phosphorylates and activates DARPP-32. Persistent elevation of mTORC1-S6K1 occludes dynamic D1R signaling downstream of DARPP-32 and blocks multiple D1R responses, including dynamic gene expression, D1R-dependent corticostriatal plasticity, and D1R behavioral responses including sociability. Candidate biomarkers of mTORC1–DARPP-32 occlusion are increased in the brain of human disease subjects in association with elevated mTORC1-S6K1, supporting a role for this mechanism in cognitive disease. Conclusions: The mTORC1-S6K1 intersection with D1R signaling provides a molecular framework to understand the effects of pathological mTORC1 activation on behavioral symptoms in neuropsychiatric disease.
URI
https://pr.ibs.re.kr/handle/8788114/10042
DOI
10.1016/j.biopsych.2020.10.012
ISSN
0006-3223
Appears in Collections:
Center for Cognition and Sociality(인지 및 사회성 연구단) > 1. Journal Papers (저널논문)
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