Journal
NEUROBIOLOGY OF DISEASE
Volume 147, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2020.105149
Keywords
Epilepsy; Calpain; Hippocampus; Inflammation; Mossy cells
Categories
Funding
- Office of the Assistant Secretary of Defense for Health Affairs through The Defense Medical Research and Development Program [W81XWH-19-1-0329, BA170606]
- Daljit and Elaine Sarkaria Chair
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The study revealed that Calpain-2 plays a critical role in epilepsy development, with its prolonged activation leading to neuropathological changes. A selective Calpain-2 inhibitor could potentially serve as a therapeutic treatment for seizure-induced neuropathology.
Calpain has been proposed to play a critical role in the development of epilepsy. Here we used conditional calpain-2 knock-out (C2CKO) mice in a C57/Bl6 background and a selective calpain-2 inhibitor to analyze the role of calpain-2 in epilepsy. Neurodegeneration was evident in various hippocampal subfields, in particular in mossy cells in the hilus of the dentate gyrus (DG) in C57/Bl6 mice 7 days after kainic acid (KA)-induced seizures. Calpain-2 activation was still observed in mossy cells 7 days after seizures. Calpain activation, astroglial and microglial activation, neurodegeneration, and cognitive impairment were absent in C2CKO mice and in C57/Bl6 mice treated with a selective calpain-2 inhibitor for 7 days after seizure initiation. Levels of the potassium chloride cotransporter 2 (KCC2) were decreased in mossy cells 7 days after seizures and this decrease was prevented by calpain-2 deletion or selective inhibition. Our results indicate that prolonged calpain-2 activation plays a critical role in neuropathology following seizures. A selective calpain-2 inhibitor could represent a therapeutic treatment for seizure-induced neuropathology.
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