title: Rapamycin reveals an mTOR-independent repression of Kv1.1 expression during epileptogenesis.
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.
authors.affiliation: Center for Learning and Memory, Department of Neuroscience, University of Texas at Austin, USA; Institute for Cell and Molecular Biology, University of Texas at Austin, USA.
authors.forename: Natasha M
authors.initials: NM
authors.lastname: Sosanya
authors.affiliation: Center for Learning and Memory, Department of Neuroscience, University of Texas at Austin, USA.
authors.forename: Darrin H
authors.initials: DH
authors.lastname: Brager
authors.affiliation: Institute for Cell and Molecular Biology, University of Texas at Austin, USA; Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin University Station C7000, Austin, TX 78712, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wolfe
authors.affiliation: Center for Learning and Memory, Department of Neuroscience, University of Texas at Austin, USA.
authors.forename: Farr
authors.initials: F
authors.lastname: Niere
authors.affiliation: Center for Learning and Memory, Department of Neuroscience, University of Texas at Austin, USA; Institute for Cell and Molecular Biology, University of Texas at Austin, USA; Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin University Station C7000, Austin, TX 78712, USA. Electronic address: Kimberly@mail.clm.utexas.edu.
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Raab-Graham
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004195:Disease Models, Animal; D051959:ELAV Proteins / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000633:toxicity; D051662:Kv1.1 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000378:metabolism / Q000494:pharmacology*; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009435:Synaptic Transmission / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors
chemical_list: D051959:ELAV Proteins; D018690:Excitatory Amino Acid Agonists; D035683:MicroRNAs; D051662:Kv1.1 Potassium Channel; D058570:TOR Serine-Threonine Kinases; D007608:Kainic Acid; D020123:Sirolimus
keywords: Potassium channels; Rapamycin; Temporal lobe epilepsy; mTOR; miRNA