Rapamycin reveals an mTOR-independent repression of Kv1.1 expression during epileptogenesis

Neurobiol Dis. 2015 Jan;73:96-105. doi: 10.1016/j.nbd.2014.09.011. Epub 2014 Sep 28.

Abstract

Changes in ion channel expression are implicated in the etiology of epilepsy. However, the molecular leading to long-term aberrant expression of ion channels are not well understood. The mechanistic/mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that mediates activity-dependent protein synthesis in neurons. mTOR is overactive in epilepsy, suggesting that excessive protein synthesis may contribute to the neuronal pathology. In contrast, we found that mTOR activity and the microRNA miR-129-5p reduce the expression of the voltage-gated potassium channel Kv1.1 in an animal model of temporal lobe epilepsy (TLE). When mTOR activity is low, Kv1.1 expression is high and the frequency of behavioral seizures is low. However, as behavioral seizure activity rises, mTOR activity increases and Kv1.1 protein levels drop. In CA1 pyramidal neurons, the reduction in Kv1.1 lowers the threshold for action potential firing. Interestingly, blocking mTOR activity with rapamycin reduces behavioral seizures and temporarily keeps Kv1.1 levels elevated. Overtime, seizure activity increases and Kv1.1 protein decreases in all animals, even those treated with rapamycin. Notably, the concentration of miR-129-5p, the negative regulator of Kv1.1 mRNA translation, increases by 21days post-status epilepticus (SE), sustaining Kv1.1 mRNA translational repression. Our results suggest that following kainic-acid induced status epilepticus there are two phases of Kv1.1 repression: (1) an initial mTOR-dependent repression of Kv1.1 that is followed by (2) a miR-129-5p persistent reduction of Kv1.1.

Keywords: Potassium channels; Rapamycin; Temporal lobe epilepsy; mTOR; miRNA.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Disease Models, Animal
  • ELAV Proteins / metabolism
  • Excitatory Amino Acid Agonists / toxicity
  • Gene Expression Regulation / drug effects*
  • Gene Expression Regulation / physiology
  • Hippocampus / drug effects
  • Hippocampus / physiology
  • In Vitro Techniques
  • Kainic Acid / toxicity
  • Kv1.1 Potassium Channel / genetics
  • Kv1.1 Potassium Channel / metabolism*
  • Male
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Patch-Clamp Techniques
  • Rats
  • Rats, Sprague-Dawley
  • Sirolimus / metabolism
  • Sirolimus / pharmacology*
  • Status Epilepticus / chemically induced
  • Status Epilepticus / drug therapy
  • Status Epilepticus / metabolism*
  • Status Epilepticus / pathology
  • Synaptic Transmission / drug effects
  • TOR Serine-Threonine Kinases / metabolism*
  • Time Factors

Substances

  • ELAV Proteins
  • Excitatory Amino Acid Agonists
  • MicroRNAs
  • Kv1.1 Potassium Channel
  • TOR Serine-Threonine Kinases
  • Kainic Acid
  • Sirolimus