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Neural Progenitor Cells Rptor Ablation Impairs Development but Benefits to Seizure-Induced Behavioral Abnormalities
Ling-Lin Chen1, Mei-Ling Wu2, Feng Zhu2
1Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Aims:
Previous study suggests that mTOR signaling pathway may play an important role in epileptogenesis. The present work was designed to explore the contribution of raptor protein to the development of epilepsy and comorbidities.
Methods:
Mice with conditional knockout of raptor protein were generated by cross-bred Rptorflox/flox mice with nestin-CRE mice. The expression of raptor protein was analyzed by Western blotting in brain tissue samples. Neuronal death and mossy fiber sprouting were detected by FJB staining and Timm staining, respectively. Spontaneous seizures were recorded by EEG-video system. Morris water maze, open field test, and excitability test were used to study the behaviors of Rptor CKO mice.
Results:
As the consequence of deleting Rptor, downstream proteins of raptor in mTORC1 signaling were partly blocked. Rptor CKO mice exhibited decrease in body and brain weight under 7 weeks old and accordingly, cortical layer thickness. After kainic acid (KA)-induced status epilepticus, overactivation of mTORC1 signaling was markedly reversed in Rptor CKO mice. Although low frequency of spontaneous seizure and seldom neuronal cell death were observed in both Rptor CKO and control littermates, KA seizure-induced mossy fiber spouting were attenuated in Rptor CKO mice. Additionally, cognitive-deficit and anxiety-like behavior after KA-induced seizures were partly reversed in Rptor CKO mice.
Conclusion:
Loss of the Rptor gene in mice neural progenitor cells affects normal development in young age and may contribute to alleviate KA seizure-induced behavioral abnormalities, suggesting that raptor protein plays an important role in seizure comorbidities.
Insights
Deleting raptor protein in mice partially blocked mTORC1 signaling, affecting development but reducing epilepsy-related comorbidities like mossy fiber sprouting and behavioral deficits after seizures.
Area of Science:
- Neuroscience
- Molecular Biology
- Epilepsy Research
Background:
- The mammalian target of rapamycin (mTOR) signaling pathway is implicated in epileptogenesis.
- Raptor is a key component of the mTOR Complex 1 (mTORC1) signaling pathway.
- The specific role of raptor protein in epilepsy and its associated comorbidities requires further investigation.
Purpose of the Study:
- To investigate the contribution of raptor protein to the development of epilepsy.
- To explore the role of raptor protein in epilepsy-related comorbidities.
- To analyze the impact of raptor deletion on mTORC1 signaling in the context of epilepsy.
Main Methods:
- Generated mice with conditional knockout of raptor protein (Rptor CKO) using Rptorflox/flox and nestin-CRE mice.
- Analyzed raptor protein expression via Western blotting.
- Assessed neuronal death (FJB staining), mossy fiber sprouting (Timm staining), spontaneous seizures (EEG-video), and behavioral changes (Morris water maze, open field test).
Main Results:
- Rptor deletion partially blocked downstream mTORC1 signaling and led to decreased body/brain weight and cortical thickness in young mice.
- In Rptor CKO mice, kainic acid (KA)-induced mTORC1 overactivation was reversed, and mossy fiber sprouting was attenuated.
- KA seizure-induced cognitive deficits and anxiety-like behaviors were partly reversed in Rptor CKO mice, despite similar spontaneous seizure frequency and neuronal death compared to controls.
Conclusions:
- Loss of the Rptor gene in neural progenitor cells impacts early development but alleviates certain behavioral abnormalities post-seizure.
- Raptor protein plays a significant role in modulating epilepsy-associated comorbidities.
- Targeting raptor-mediated mTORC1 signaling may offer therapeutic potential for epilepsy comorbidities.
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