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2017 | 77 | Suppl.1 |
Tytuł artykułu

Regulation and cellular functions of mTORC1 in animal models of epilepsy

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Języki publikacji
Introduction: Mammalian target of rapamycin (mTOR) is a protein kinase that regulates cellular metabolism. Adequate mTOR activity is needed for development as well as proper physiology of mature neurons. Changes in mTOR activity are often observed in neuropathology. Several groups reported that seizures increase mTOR activity, and mTOR contributes to spontaneous seizures. However, the current knowledge about 1) the spatiotemporal and 2) the subcellular pattern of mTOR activation as well as 3) mTOR downstream effectorsin epilepsy is limited. Effects of mTOR insufficiency in seizures also remain under investigated. Aim: The aim of my team is to understand regulation and contribution of mTOR to epilepsy and pinpointing cellular mechanisms downstream mTOR. Methods: To study a role of mTOR in epilepsy we used models of pharmacological treatment with kainic acid (KA). We performed analysis of status epilepticus (SE) severity and progression. We analyzed with quantitative Western-blot and microarrays changes in signaling pathways and gene expression. Subcellular distribution of mTOR and its activity was analyzed by live microscopy. Results: We showed that SE induces mTOR first in neurons and next in astrocytes. At early times post seizures mTOR translocates to the nucleus, where its activity increases gradually. We showed that mTOR is involved in KA-dependent gene expression and genes regulated by mTOR regulate cytoskeleton. One of them, Elmo-1 regulates axonal growth and dendritic spine changes. Our research shows also that insufficient mTOR activity lead to increased sensitivity to KA. Conclusions: mTOR is an important player in epilepsy. One of the processes likely controlled by mTOR in epilepsy is transcription of genes responsible for cytoskeleton rearrangement. On the other hand, insufficient mTOR activity decreases threshold for epileptic-like neuronal activity. FINANCIAL SUPPORT: The research was supported by Polish National Science Centre (grants no. 2012/05/B/ NZ3/00429; 2012/07/E/NZ3/00503), 7FP grant (no. 602391, “EPISTOP”) and the Polish Ministerial funds for science (years 2014–2018) for the implementation of international co‑financed project. JJ is a recipient of the Foundation for Polish Science “Mistrz” Professorial Subsidy.
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  • International Institute of Molecular and Cell Biology, Warsaw, Poland
  • International Institute of Molecular and Cell Biology, Warsaw, Poland
  • International Institute of Molecular and Cell Biology, Warsaw, Poland
  • International Institute of Molecular and Cell Biology, Warsaw, Poland
  • Children’s Memorial Health Institute, Department of Neurology and Epileptology, Warsaw, Poland
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