Calpain protease mediates axonal degeneration induced in a model of Status epilepticus.

UNSAIN, NICOLÁS; MONTROULL L.,; DANIEL MASCÒ; DANELON, VICTOR; BARKER, PHILL

MOLECULAR AND CELLULAR NEUROSCIENCES.

ACADEMIC PRESS INC ELSEVIER SCIENCE

Lugar: Amsterdam; Año: 2016 vol. 75 p. 81 - 92

1044-7431

Recent findings indicate that the mechanisms that drive reshaping of the nervous system are aberrantly activatedin epilepsy and several neurodegenerative diseases. The recurrent seizures in epilepsy, particularly in the condition called status epilepticus, can cause permanent neurological damage, resulting in cognitive dysfunction andother serious neurological conditions. In this study, we used an in vitro model of status epilepticus to examinethe role of calpain in the degeneration of hippocampal neurons. We grew neurons on a culture system thatallowed studying the dendritic and axonal domains separately from the cell bodies. We found that a recentlycharacterized calpain substrate, the neurotrophin receptor TrkB, is cleaved in the dendritic and axonal domainof neurons committed to die, and this constitutes an early step in the neuronal degeneration process. Whilethe full-length TrkB (TrkB-FL) levels decreased, the truncated form of TrkB (Tc TrkB-FL) concurrently increased,leading to a TrkB-FL/Tc TrkB-FL imbalance, which is thought to be causally linked to neurodegeneration. We further show that the treatment with N-acetyl-Leu-Leu-norleucinal, a specific calpain activity blocker, fully protectsthe neuronal processes from degeneration, prevents the TrkB-FL/Tc TrkB-FL imbalance, and provides full neuroprotection. Moreover, the use of the TrkB antagonist ANA 12 at the time when the levels of TrkB-FL were significantly decreased, totally blocked neuronal death, suggesting that Tc TrkB-FL may have a role in neuronal death.These results indicate that the imbalance of these neurotrophins receptors plays a key role in neurite degeneration induced by seizures.