Spatiotemporal characterization of mTOR kinase activity following kainic acid induced status epilepticus and analysis of rat brain response to chronic rapamycin treatment

Matylda Macias; Magdalena Blazejczyk; Paulina Kazmierska; Bartosz Caban; Agnieszka Skalecka; Bartosz Tarkowski; Anna Rodo; Jan Konopacki; Jacek Jaworski

doi:10.1371/journal.pone.0064455

Spatiotemporal characterization of mTOR kinase activity following kainic acid induced status epilepticus and analysis of rat brain response to chronic rapamycin treatment

PLoS One. 2013 May 28;8(5):e64455. doi: 10.1371/journal.pone.0064455. Print 2013.

Authors

Matylda Macias¹, Magdalena Blazejczyk, Paulina Kazmierska, Bartosz Caban, Agnieszka Skalecka, Bartosz Tarkowski, Anna Rodo, Jan Konopacki, Jacek Jaworski

Affiliation

¹ Laboratory of Molecular and Cell Neurobiology, International Institute of Molecular and Cell Biology, Warsaw, Poland.

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

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Astrocytes / drug effects
Astrocytes / metabolism
Astrocytes / pathology
Brain / drug effects
Brain / enzymology
Brain / pathology*
Cell Death / drug effects
Cell Nucleus / drug effects
Cell Nucleus / enzymology
Hippocampus / drug effects
Hippocampus / pathology
Kainic Acid
Male
Neurons / drug effects
Neurons / enzymology
Phosphorylation / drug effects
Phosphoserine / metabolism
Rats
Rats, Wistar
Ribosomal Protein S6 / metabolism
Seizures / drug therapy
Seizures / pathology
Signal Transduction / drug effects
Sirolimus / administration & dosage
Sirolimus / pharmacology
Sirolimus / therapeutic use*
Spatio-Temporal Analysis*
Status Epilepticus / chemically induced
Status Epilepticus / drug therapy*
Status Epilepticus / enzymology*
Status Epilepticus / pathology
Subcellular Fractions / drug effects
Subcellular Fractions / metabolism
TOR Serine-Threonine Kinases / metabolism*

Substances

Ribosomal Protein S6
Phosphoserine
TOR Serine-Threonine Kinases
Kainic Acid
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.