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

Sosanya, Natasha M.; Brager, Darrin H.; Wolfe, Sarah; Niere, Farr; Raab-Graham, Kimberly F.

doi:10.1016/j.nbd.2014.09.011

Cited by 49Epilepsy research and treatmentIon channel regulation and functionNeuroscience and Neuropharmacology Research

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

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Sosanya, Natasha M., Brager, Darrin H., Wolfe, Sarah, Niere, Farr, Raab-Graham, Kimberly F.·2015·Neurobiology of Disease

DOI 10.1016/j.nbd.2014.09.011

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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 i…

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Epilepsy, which is common in AD and ASD, has enhanced mTORC1 activity.
“Furthermore, epilepsy, which is common in AD and ASD, has enhanced mTORC1 activity (28 -32).”
From Analysis of proteins that rapidly change upon mechanistic/mammalian target of rapamycin complex 1 (mTORC1) repression identifies parkinson protein 7 (PARK7) as a novel protein aberrantly expressed in tuberous sclerosis complex (TSC) (2016) · cites this paper as [31]
Kv1.1 protein (Kcna1) was only detected in the soluble fraction when mTORC1 was repressed.
“As expected, Kv1.1 protein (Kcna1) was only detected in the soluble fraction when mTORC1 was repressed, confirming our previous findings (31,34,35).”
From Analysis of proteins that rapidly change upon mechanistic/mammalian target of rapamycin complex 1 (mTORC1) repression identifies parkinson protein 7 (PARK7) as a novel protein aberrantly expressed in tuberous sclerosis complex (TSC) (2016) · cites this paper as [31]
In models of temporal lobe epilepsy there is a reduction in the expression of voltage-gated ion channels including Kv1.1.
“Consistent with these results, in models of temporal lobe epilepsy there is a reduction in the expression of voltage-gated ion channels including Kv1.1 (30,31,36).”
From Analysis of proteins that rapidly change upon mechanistic/mammalian target of rapamycin complex 1 (mTORC1) repression identifies parkinson protein 7 (PARK7) as a novel protein aberrantly expressed in tuberous sclerosis complex (TSC) (2016) · cites this paper as [31]

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Authors: Sosanya, N. M., Brager, D. H., Wolfe, S., Niere, F., & Raab-Graham, K. F.
Affiliations: The University of Texas at Austin (US)
ORCID: Sosanya, Natasha M.
Brager, Darrin H.
Wolfe, Sarah
Niere, Farr
Raab-Graham, Kimberly F.
Venue: Neurobiology of Disease
Publisher: Elsevier BV
Published: 2015-01
Volume: 73
Pages: 96-105
ISSN: 0969-9961 (ISSN-L)
DOI: 10.1016/j.nbd.2014.09.011
OpenAlex: W1971473062
Cited by: 49
References: 44
Citations by year: 2026: 4 · 2025: 1 · 2024: 5 · 2023: 4 · 2022: 2 · 2021: 3 · 2020: 7 · 2019: 2 · 2018: 4 · 2017: 6 · 2016: 6 · 2015: 5
FWCI: 4.32
Type: journal article
Language: en
Open access: green
doaj.org
Licence: cc-by-sa
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Neurobiology of Disease (publishedVersion)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: NSF (IOS 1026527, IOS 1355158, PRFB 1306528)
Department of Defense USAMRMC Award (W81XWH-14-1-0061)
University of Texas Research
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: Kv1.1, mTOR, rapamycin, miR-129-5p, epileptogenesis, temporal lobe epilepsy, status epilepticus, kainic acid, voltage-gated potassium channels, CA1 pyramidal neurons, behavioral seizures
MeSH terms: Action Potentials, Animals, Disease Models, Animal, Gene Expression Regulation, Hippocampus, Kainic Acid, Male, Synaptic Transmission, Status Epilepticus, Time Factors, Rats, Sprague-Dawley, Patch-Clamp Techniques, Excitatory Amino Acid Agonists, Sirolimus, MicroRNAs, Rats, Kv1.1 Potassium Channel, ELAV Proteins, TOR Serine-Threonine Kinases, In Vitro Techniques

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

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