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Cited by 266Epilepsy research and treatmentNeurogenesis and neuroplasticity mechanismsPharmacological Effects and Toxicity Studies

Excessive activation of mTOR in postnatally generated granule cells is sufficient to cause epilepsy

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Pun, Raymund Y.K., Rolle, Isaiah J., LaSarge, Candi L., Hosford, Bethany E., Rosen, Jules M., Uhl, Juli D., Schmeltzer, Sarah N., Faulkner, Christian +5 more·2012·Neuron
DOI 10.1016/j.neuron.2012.08.002PMC PMC3474536
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Abstract

The dentate gyrus is hypothesized to function as a "gate," limiting the flow of excitation through the hippocampus. During epileptogenesis, adult-generated granule cells (DGCs) form aberrant neuronal connections with neighboring DGCs, disrupting the dentate gate. Hyperactivation of the mTOR signaling pathway is implicated in driving this aberrant circuit formation. While the presence of abnormal DGCs in epilepsy has been known for decades, direct evidence linking abnormal DGCs to seizures has been lacking. Here, we isolate the effects of abnormal DGCs using a transgenic mouse model to selectively delete PTEN from postnatally generated DGCs. PTEN deletion led to hyperactivation of the mTOR pathway, producing abnormal DGCs morphologically similar to those in epilepsy. Strikingly, animals in which PTEN was deleted from ≥ 9% of the DGC population developed spontaneous seizures in about 4 weeks, confirming that abnormal DGCs, which are present in both animals and humans with epilepsy, are capable of causing the disease.

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Authors
Pun, R. Y. K., Rolle, I. J., LaSarge, C. L., Hosford, B. E., Rosen, J. M., Uhl, J. D., Schmeltzer, S. N., Faulkner, C., Bronson, S. L., Murphy, B. L., Richards, D. A., Holland, K. D., & Danzer, S. C.
Affiliations
  • Cincinnati Children's Hospital Medical Center (US)
  • University of Cincinnati (US)
Corresponding author
Danzer, Steve C.
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2012-09
Volume
75
Issue
6
Pages
1022-1034
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2012.08.002
PMC
PMC3474536
OpenAlex
W1985950007
Cited by
266
References
67
Citations by year
2026: 7 · 2025: 14 · 2024: 20 · 2023: 14 · 2022: 14 · 2021: 13 · 2020: 19 · 2019: 20 · 2018: 19 · 2017: 25 · 2016: 35 · 2015: 27 · 2014: 23 · 2013: 14 · 2012: 2
FWCI
15.08
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Hospital Research Foundation
  • Korea Electrotechnology Research Institute
  • National Institute of Neurological Disorders and Stroke (R01NS065020, T32NS007453, R01NS062806)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
Keywords
mTOR signaling, PTEN deletion, dentate gyrus, epileptogenesis, spontaneous seizures, hippocampus, transgenic mouse model
MeSH terms
Zinc Finger Protein GLI1, Disks Large Homolog 4 Protein, Animals, Animals, Newborn, Carrier Proteins, Disease Models, Animal, Electroencephalography, Epilepsy, Gene Expression Regulation, Gliosis, Immunosuppressive Agents, Membrane Proteins, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Olfactory Pathways, Phosphopyruvate Hydratase, Time Factors, Dentate Gyrus, Mossy Fibers, Hippocampal, Sirolimus, Membrane Transport Proteins, Cation Transport Proteins, Green Fluorescent Proteins, PTEN Phosphohydrolase, Mice, Guanylate Kinases, Kruppel-Like Transcription Factors, TOR Serine-Threonine Kinases

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