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

Autor: Gum Hwa Lee, Alena Savonenko, Paul F. Worley, Po Yu Chen, Susan M. Resnick, Bo Xiao, Joo Min Park, Kevin T. Chen, David J. Linden, Chan Hyun Na, Karen K. Szumlinski, Raozhou Lin, Lisa N. Learman, Akhilesh Pandey, Juan C. Troncoso, Santosh Renuse
Rok vydání: 2021
Předmět:
0301 basic medicine
Dopamine and cAMP-Regulated Phosphoprotein 32
P70-S6 Kinase 1
mTORC1
Mechanistic Target of Rapamycin Complex 1
Medical and Health Sciences
Immediate early gene
03 medical and health sciences
0302 clinical medicine
Dopamine
Dopamine D1
Receptors
Behavioral and Social Science
medicine
Humans
2.1 Biological and endogenous factors
Social behavior
Phosphorylation
Aetiology
Biological Psychiatry
Psychiatry
biology
Kinase
Ribosomal Protein S6 Kinases
TOR Serine-Threonine Kinases
Psychology and Cognitive Sciences
Neurosciences
S6K1
Biological Sciences
DARPP-32
Brain Disorders
030104 developmental biology
Dopamine receptor
Neurological
D(1) dopamine receptor
biology.protein
biological phenomena
cell phenomena
and immunity
Neuroscience
030217 neurology & neurosurgery
Signal Transduction
RHEB
medicine.drug
Zdroj: Biological psychiatry, vol 89, iss 11
ISSN: 0006-3223
DOI: 10.1016/j.biopsych.2020.10.012
Popis: 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. 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.
Databáze: OpenAIRE
Externí odkaz: