Abstract
Mammalian target of rapamycin (mTOR) is a protein kinase that senses nutrient availability, trophic factors support, cellular energy level, cellular stress, and neurotransmitters and adjusts cellular metabolism accordingly. Adequate mTOR activity is needed for development as well as proper physiology of mature neurons. Consequently, changes in mTOR activity are often observed in neuropathology. Recently, several groups reported that seizures increase mammalian target of rapamycin (mTOR) kinase activity, and such increased activity in genetic models can contribute to spontaneous seizures. However, the current knowledge about the spatiotemporal pattern of mTOR activation induced by proconvulsive agents is rather rudimentary. Also consequences of insufficient mTOR activity on a status epilepticus are poorly understood. Here, we systematically investigated these two issues. We showed that mTOR signaling was activated by kainic acid (KA)-induced status epilepticus through several brain areas, including the hippocampus and cortex as well as revealed two waves of mTOR activation: an early wave (2 h) that occurs in neurons and a late wave that predominantly occurs in astrocytes. Unexpectedly, we found that pretreatment with rapamycin, a potent mTOR inhibitor, gradually (i) sensitized animals to KA treatment and (ii) induced gross anatomical changes in the brain.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Astrocytes / drug effects
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Astrocytes / metabolism
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Astrocytes / pathology
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Brain / drug effects
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Brain / enzymology
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Brain / pathology*
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Cell Death / drug effects
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Cell Nucleus / drug effects
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Cell Nucleus / enzymology
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Hippocampus / drug effects
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Hippocampus / pathology
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Kainic Acid
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Male
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Neurons / drug effects
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Neurons / enzymology
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Phosphorylation / drug effects
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Phosphoserine / metabolism
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Rats
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Rats, Wistar
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Ribosomal Protein S6 / metabolism
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Seizures / drug therapy
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Seizures / pathology
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Signal Transduction / drug effects
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Sirolimus / administration & dosage
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Sirolimus / pharmacology
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Sirolimus / therapeutic use*
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Spatio-Temporal Analysis*
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Status Epilepticus / chemically induced
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Status Epilepticus / drug therapy*
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Status Epilepticus / enzymology*
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Status Epilepticus / pathology
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Subcellular Fractions / drug effects
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Subcellular Fractions / metabolism
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TOR Serine-Threonine Kinases / metabolism*
Substances
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Ribosomal Protein S6
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Phosphoserine
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TOR Serine-Threonine Kinases
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Kainic Acid
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Sirolimus
Grants and funding
This work was supported by a Polish-Norwegian Research Fund grant (PNRF - 96 - A I - 1/07), ERA-NET-NEURON/03/2010 grant (co-financed by the National Centre for Research and Development), FP7-HealthProt grant (#229676) and Polish National Science Center OPUS grant (2012/05/B/NZ3/00429). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.