ECS Inhibits the mTOR Signaling Pathway via AMPK in the Rat Frontal Cortex: New Study From Korea

 Out on PubMed, from scientists in Korea, is this study:

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

Kim SH, Yu HS, Huh S, Kang UG, Kim YS.Psychopharmacology (Berl). 2021 Oct 30. doi: 10.1007/s00213-021-06015-2. Online ahead of print.PMID: 34716784

Psychopharmacology  

https://doi.org/10.1007/s00213-021-06015-2 

ORIGINAL INVESTIGATION 

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

Se Hyun Kim1  · Hyun Sook Yu2 · Seonghoo Huh2 · Ung Gu Kang1,3 · Yong Sik Kim4 

Received: 15 July 2021 / Accepted: 13 October 2021 

© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021 

The abstract is copied below:

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.

Keywords: AMP-activated protein kinase; Electroconvulsive therapy; Mammalian target of rapamycin.

The pdf is here.

The point of today's blog post is to shine light on the fact that basic science investigation into the mechanism of action of ECT is alive and well. The details, while interesting, are less important than the overall concepts of the powerful brain mechanisms set into play by ECS (and, by extension, ECT in humans).  The mTOR pathway story is certainly fascinating; time will tell if these findings are replicated, and if they prove central to an understanding of the antidepressant and antipsychotic effects of ECT. Elucidating the mechanism of action of ECT is not only scientifically important (it may lead to a better understanding of the etiology of psychiatric illness itself), but it will help silence critics who contend that not fully understanding how a treatment works is reason not to use it, despite decades of empirical evidence for efficacy and safety. Applying that standard equally amongst all medical treatments would lead to some serious curtailment of modern medicine...

For those with a basic science bent, a full read of this paper, with multiple elaborate experiments, will be ~35 minutes.