Electroconvulsive seizure inhibits the mTOR signaling pathway via AMPK in the rat frontal cortex

Rationale Accumulating evidence indicates critical involvement of mammalian target of rapamycin (mTOR) in the treatment of depressive disorders, epilepsy, and neurodegenerative disorders through its signal transduction mechanisms related to protein translation, autophagy, and synaptic remodeling. El...

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Published in:Psychopharmacology 2022-02, Vol.239 (2), p.443-454
Main Authors: Kim, Se Hyun, Yu, Hyun Sook, Huh, Seonghoo, Kang, Ung Gu, Kim, Yong Sik
Format: Article
Language:English
Subjects:
AKT protein
AMP-Activated Protein Kinases - metabolism
Animals
Antidepressants
Autophagy
Biomedical and Life Sciences
Biomedicine
Birds of prey
Care and treatment
Cellular signal transduction
Convulsions & seizures
Cortex (frontal)
Electroconvulsive therapy
Epilepsy
Extracellular signal-regulated kinase
Frontal Lobe - metabolism
Health aspects
Kinases
Mechanistic Target of Rapamycin Complex 1 - metabolism
Mental disorders
Mental illness
Neurodegenerative diseases
Neuroprotection
Neurosciences
Original Investigation
Patient outcomes
Pharmacology/Toxicology
Phosphorylation
Protein kinases
Psychiatry
Rapamycin
Rats
Seizures
Signal Transduction
TOR protein
TOR Serine-Threonine Kinases - metabolism
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Summary:Rationale Accumulating evidence indicates critical involvement of mammalian target of rapamycin (mTOR) in the treatment of depressive disorders, epilepsy, and neurodegenerative disorders through its signal transduction mechanisms related to protein translation, autophagy, and synaptic remodeling. Electroconvulsive seizure (ECS) treatment is a potent antidepressive, anti-convulsive, and neuroprotective therapeutic modality; however, its effects on mTOR signaling have not yet been clarified. Methods The effect of ECS on the mTOR complex 1 (mTORC1) pathway was investigated in the rat frontal cortex. ECS or sham treatment was administered once per day for 10 days (E10X or sham), and compound C was administered through the intracerebroventricular cannula. Changes in mTORC1-associated signaling molecules and their interactions were analyzed. Results E10X reduced phosphorylation of mTOR downstream substrates, including p70S6K, S6, and 4E-BP1, and increased inhibitory phosphorylation of mTOR at Thr2446 compared to the sham group in the rat frontal cortex, indicating E10X-induced inhibition of mTORC1 activity. Akt and ERK1/2, upstream kinases that activate mTORC1, were not inhibited; however, AMPK, which can inhibit mTORC1, was activated. AMPK-responsive phosphorylation of Raptor at Ser792 and TSC2 at Ser1387 inhibiting mTORC1 was increased by E10X. Moreover, intrabrain inhibition of AMPK restored E10X-induced changes in the phosphorylation of S6, Raptor, and TSC2, indicating mediation of AMPK in E10X-induced mTOR inhibition. Conclusions Repeated ECS treatments inhibit mTORC1 signaling by interactive crosstalk between mTOR and AMPK pathways, which could play important roles in the action of ECS via autophagy induction.
ISSN:0033-3158
1432-2072
DOI:10.1007/s00213-021-06015-2