Wortmannin Attenuates Seizure-Induced Hyperactive PI3K/Akt/mTOR Signaling, Impaired Memory, and Spine Dysmorphology in Rats

Numerous studies have shown epilepsy-associated cognitive deficits, but less is known about the effects of one single generalized seizure. Recent studies demonstrate that a single, self-limited seizure can result in memory deficits and induces hyperactive phosphoinositide 3-kinase/Akt (protein kinas...

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Bibliographic Details
Published in:eNeuro 2017-05, Vol.4 (3), p.ENEURO.0354-16.2017
Main Authors: Carter, Angela N, Born, Heather A, Levine, Amber T, Dao, An T, Zhao, Amanda J, Lee, Wai L, Anderson, Anne E
Format: Article
Language:English
Subjects:
Androstadienes - therapeutic use
Animals
Animals, Newborn
Convulsants - toxicity
Dendritic Spines - drug effects
Dendritic Spines - ultrastructure
Disease Models, Animal
Enzyme Inhibitors - pharmacology
Fear
Female
Male
Memory Disorders - drug therapy
Memory Disorders - etiology
New Research
Pentylenetetrazole - toxicity
Phosphatidylinositol 3-Kinases - metabolism
Protein Kinase Inhibitors - therapeutic use
Proto-Oncogene Proteins c-akt - metabolism
Rats
Rats, Sprague-Dawley
Seizures - chemically induced
Seizures - complications
Seizures - pathology
Signal Transduction - drug effects
Signal Transduction - physiology
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Summary:Numerous studies have shown epilepsy-associated cognitive deficits, but less is known about the effects of one single generalized seizure. Recent studies demonstrate that a single, self-limited seizure can result in memory deficits and induces hyperactive phosphoinositide 3-kinase/Akt (protein kinase B)/mechanistic target of rapamycin (PI3K/Akt/mTOR) signaling. However, the effect of a single seizure on subcellular structures such as dendritic spines and the role of aberrant PI3K/Akt/mTOR signaling in these seizure-induced changes are unclear. Using the pentylenetetrazole (PTZ) model, we induced a single generalized seizure in rats and: (1) further characterized short- and long-term hippocampal and amygdala-dependent memory deficits, (2) evaluated whether there are changes in dendritic spines, and (3) determined whether inhibiting hyperactive PI3K/Akt/mTOR signaling rescued these alterations. Using the PI3K inhibitor wortmannin (Wort), we partially rescued short- and long-term memory deficits and altered spine morphology. These studies provide evidence that pathological PI3K/Akt/mTOR signaling plays a role in seizure-induced memory deficits as well as aberrant spine morphology.
ISSN:2373-2822
2373-2822
DOI:10.1523/ENEURO.0354-16.2017