Related Experiment Video
Updated: Feb 15, 2026
Anteromesial Temporal Lobectomy for Medically Intractable Temporal Lobe Epilepsy: An Operative Study
Published on: August 15, 2025
Mechanistic target of rapamycin complex 1 and 2 in human temporal lobe epilepsy
Delia M Talos1, Leah M Jacobs1, Sarah Gourmaud1
1Department of Neurology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA.
Objective:
Temporal lobe epilepsy (TLE) is a chronic epilepsy syndrome defined by seizures and progressive neurological disabilities, including cognitive impairments, anxiety, and depression. Here, human TLE specimens were investigated focusing on the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) and complex 2 (mTORC2) activities in the brain, given that both pathways may represent unique targets for treatment.
Methods:
Surgically resected hippocampal and temporal lobe samples from therapy-resistant TLE patients were analyzed by western blotting to quantify the expression of established mTORC1 and mTORC2 activity markers and upstream or downstream signaling pathways involving the two complexes. Histological and immunohistochemical techniques were used to assess hippocampal and neocortical structural abnormalities and cell-specific expression of individual biomarkers. Samples from patients with focal cortical dysplasia (FCD) type II served as positive controls.
Results:
We found significantly increased expression of phospho-mTOR (Ser2448), phospho-S6 (Ser235/236), phospho-S6 (Ser240/244), and phospho-Akt (Ser473) in TLE samples compared to controls, consistent with activation of both mTORC1 and mTORC2. Our work identified the phosphoinositide 3-kinase and Ras/extracellular signal-regulated kinase signaling pathways as potential mTORC1 and mTORC2 upstream activators. In addition, we found that overactive mTORC2 signaling was accompanied by induction of two protein kinase B-dependent prosurvival pathways, as evidenced by increased inhibitory phosphorylation of forkhead box class O3a (Ser253) and glycogen synthase kinase 3 beta (Ser9).
Interpretation:
Our data demonstrate that mTOR signaling is significantly dysregulated in human TLE, offering new targets for pharmacological interventions. Specifically, clinically available drugs that suppress mTORC1 without compromising mTOR2 signaling, such as rapamycin and its analogs, may represent a new group of antiepileptogenic agents in TLE patients. Ann Neurol 2018;83:311-327.
Insights
Dysregulated mechanistic target of rapamycin (mTOR) signaling, including mTORC1 and mTORC2, is evident in temporal lobe epilepsy (TLE). Rapamycin analogs may offer new therapeutic strategies for TLE patients.
Area of Science:
- Neuroscience
- Molecular Biology
- Epilepsy Research
Background:
- Temporal lobe epilepsy (TLE) is a chronic neurological disorder characterized by seizures and progressive neurological deficits.
- Current treatments for TLE are often ineffective, necessitating the exploration of novel therapeutic targets.
Purpose of the Study:
- To investigate the activity of mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) and complex 2 (mTORC2) in human TLE specimens.
- To identify potential therapeutic targets within the mTOR signaling pathways for TLE treatment.
Main Methods:
- Analysis of surgically resected hippocampal and temporal lobe samples from therapy-resistant TLE patients.
- Western blotting to quantify mTORC1 and mTORC2 activity markers and associated signaling pathways.
- Histological and immunohistochemical techniques to assess structural abnormalities and cell-specific biomarker expression.
Main Results:
- Significantly increased expression of phospho-mTOR, phospho-S6, and phospho-Akt was observed in TLE samples, indicating activation of both mTORC1 and mTORC2.
- Identification of phosphoinositide 3-kinase and Ras/extracellular signal-regulated kinase pathways as potential upstream activators of mTORC1 and mTORC2.
- Overactive mTORC2 signaling correlated with the induction of prosurvival pathways, including phosphorylation of FOXO3a and GSK3 beta.
Conclusions:
- mTOR signaling is significantly dysregulated in human TLE, presenting novel targets for pharmacological intervention.
- Clinically available mTORC1 inhibitors, like rapamycin, may serve as effective antiepileptogenic agents in TLE patients by targeting specific mTOR pathways.
More Related Videos
Related Concept Videos
02:27Predicting Products: SN1 vs. SN2
With increased substitution on the alkyl halide,...
01:22Lobes of the Cerebrum
Frontal lobe
The frontal lobes, located behind the forehead, are the command center of our brain, controlling personality, intelligence, and voluntary muscle movements....
02:46Crystal Field Theory - Tetrahedral and Square Planar Complexes
Crystal field theory (CFT) is applicable to molecules in geometries other than octahedral. In octahedral complexes, the lobes of the dx2−y2 and dz2 orbitals point directly at the ligands. For tetrahedral complexes, the d orbitals remain in place, but with only four ligands located between the axes. None of the orbitals points directly at the tetrahedral ligands. However, the dx2−y2 and dz2 orbitals (along the Cartesian axes) overlap with the ligands less than the dxy,...
02:58Crystal Field Theory - Octahedral Complexes
To explain the observed behavior of transition metal complexes (such as colors), a model involving electrostatic interactions between the electrons from the ligands and the electrons in the unhybridized d orbitals of the central metal atom has been developed. This electrostatic model is crystal field theory (CFT). It helps to understand, interpret, and predict the colors, magnetic behavior, and some structures of coordination compounds of transition metals.
CFT focuses on...
01:261° Amines to Diazonium or Aryldiazonium Salts: Diazotization with NaNO2 Overview
The nitrous acid is unstable. Hence, it is formed in situ from a solution of sodium nitrite and cold aqueous acids such as hydrochloric or sulfuric acid. In an acidic solution, the –OH group of nitrous acid undergoes protonation to give oxonium ion, followed by...
01:371° Amines to Diazonium or Aryldiazonium Salts: Diazotization with NaNO2 Mechanism