Persistently Elevated mTOR Complex 1-S6 Kinase 1 Disrupts DARPP-32-Dependent D1 Dopamine Receptor Signaling and Behaviors

Lin, Raozhou1; Learman, Lisa N.1; Na, Chan-Hyun2,3; Renuse, Santosh5,6; Chen, Kevin T.1; Chen, Po Yu1; Lee, Gum-Hwa1,11; Xiao, Bo1,12; Resnick, Susan M.7; Troncoso, Juan C.2,4; Szumlinski, Karen K.8,9; Linden, David J.1; Park, Joo-Min10; Savonenko, Alena4; Pandey, Akhilesh5,6; Worley, Paul F.1,2

2021-06-01

10.1016/j.biopsych.2020.10.012

BIOLOGICAL PSYCHIATRY   影响因子和分区

0006-3223

1873-2402

BACKGROUND: The serine-threonine kinase mTORC1 (mechanistic 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. C ONCLUSIONS: 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. https://doi.org/10.1016/j.biopsych.2020.10.012

SCI

英语

其他

National Institutes of Health["R01 DA010309","P50DA044123"]

Neurosciences & Neurology ; Psychiatry

Neurosciences ; Psychiatry

WOS:000675832500009

ELSEVIER SCIENCE INC

NEUROSCIENCE & BEHAVIOR

Web of Science

1.Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA
2.Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA
3.Johns Hopkins Univ, Sch Med, Inst Cell Engn, Baltimore, MD USA
4.Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA
5.Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA
6.Mayo Clin, Ctr Individualized Med, Rochester, MN USA
7.NIA, Lab Behav Neurosci, Baltimore, MD 21224 USA
8.Univ Calif Santa Barbara, Dept Psychol & Brain Sci, Santa Barbara, CA 93106 USA
9.Univ Calif Santa Barbara, Neurosci Res Inst, Santa Barbara, CA 93106 USA
10.Inst for Basic Sci Korea, Ctr Cognit & Social, Daejeon, South Korea
11.Chosun Univ, Coll Pharm, Gwangju, South Korea
12.Southern Univ Sci & Technol, Dept Biol, Shenzhen, Peoples R China

Lin, Raozhou,Learman, Lisa N.,Na, Chan-Hyun,et al. Persistently Elevated mTOR Complex 1-S6 Kinase 1 Disrupts DARPP-32-Dependent D1 Dopamine Receptor Signaling and Behaviors[J]. BIOLOGICAL PSYCHIATRY,2021,89(11).

Lin, Raozhou.,Learman, Lisa N..,Na, Chan-Hyun.,Renuse, Santosh.,Chen, Kevin T..,...&Worley, Paul F..(2021).Persistently Elevated mTOR Complex 1-S6 Kinase 1 Disrupts DARPP-32-Dependent D1 Dopamine Receptor Signaling and Behaviors.BIOLOGICAL PSYCHIATRY,89(11).

Lin, Raozhou,et al."Persistently Elevated mTOR Complex 1-S6 Kinase 1 Disrupts DARPP-32-Dependent D1 Dopamine Receptor Signaling and Behaviors".BIOLOGICAL PSYCHIATRY 89.11(2021).