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Updated: Feb 23, 2026
A Behavioral Screen for Heat-Induced Seizures in Mouse Models of Epilepsy
Published on: July 12, 2021
RHEB1 insufficiency in aged male mice is associated with stress-induced seizures
Qi Tian1, Pavel Gromov2, Joachim H Clement3
1OHSU Transgenic Mouse Models Shared Resource, Knight Cancer Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
Abstract:
The mechanistic target of rapamycin (mTOR), a protein kinase, is a central regulator of mammalian metabolism and physiology. Protein mTOR complex 1 (mTORC1) functions as a major sensor for the nutrient, energy, and redox state of a cell and is activated by ras homolog enriched in brain (RHEB1), a GTP-binding protein. Increased activation of mTORC1 pathway has been associated with developmental abnormalities, certain form of epilepsy (tuberous sclerosis), and cancer. Clinically, those mTOR-related disorders are treated with the mTOR inhibitor rapamycin and its rapalogs. Because the effects of chronic interference with mTOR signaling in the aged brain are yet unknown, we used a genetic strategy to interfere with mTORC1 signaling selectively by introducing mutations of Rheb1 into the mouse. We created conventional knockout (Rheb1 +/- ) and gene trap (Rheb1 Δ/+ ) mutant mouse lines. Rheb1-insufficient mice with different combinations of mutant alleles were monitored over a time span of 2 years. The mice did not show any behavioral/neurological changes during the first 18 months of age. However, after aging (> 18 months of age), both the Rheb1 +/- and Rheb1 Δ /- hybrid males developed rare stress-induced seizures, whereas Rheb1 +/- and Rheb1 Δ /- females and Rheb1 Δ/+ and Rheb1 Δ/Δ mice of both genders did not show any abnormality. Our findings suggest that chronic intervention with mTORC1 signaling in the aged brain might be associated with major adverse events.
Insights
Chronic interference with mTORC1 signaling in aged male mice, specifically Rheb1-insufficient models, led to stress-induced seizures after 18 months of age, suggesting potential adverse events in the aging brain.
Area of Science:
- Neuroscience
- Molecular Biology
- Aging Research
Background:
- The mechanistic target of rapamycin (mTOR) pathway, particularly mTOR complex 1 (mTORC1), regulates cellular metabolism and is implicated in various diseases.
- mTORC1 activation is influenced by nutrient, energy, and redox states, and is mediated by the GTP-binding protein RHEB1.
- Dysregulation of the mTORC1 pathway is linked to developmental disorders, epilepsy, and cancer, often treated with mTOR inhibitors like rapamycin.
Purpose of the Study:
- To investigate the long-term effects of chronic mTORC1 signaling interference in the aged brain.
- To determine if genetic manipulation of RHEB1 in mice leads to age-related neurological or behavioral changes.
Main Methods:
- Creation of conventional knockout (Rheb1+/-) and gene trap (Rheb1Δ/+) mutant mouse lines.
- Monitoring of Rheb1-insufficient mice with varying mutant allele combinations over a 2-year period.
- Assessment of behavioral and neurological changes, with a focus on seizure activity in aged mice.
Main Results:
- No significant behavioral or neurological changes were observed in mice during the first 18 months of age.
- Aged Rheb1+/- and Rheb1Δ/- hybrid males (over 18 months) exhibited rare stress-induced seizures.
- No abnormalities were noted in Rheb1+/- and Rheb1Δ/- females or Rheb1Δ/+ and Rheb1Δ/Δ mice of either gender.
Conclusions:
- Chronic interference with mTORC1 signaling via Rheb1 insufficiency in the aged brain may be associated with adverse neurological events, specifically seizures in males.
- These findings highlight potential risks of long-term mTOR pathway modulation in aging.
