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Death mechanisms compromising hippocampal neurogenesis after status epilepticus

Ekdahl Clementson, Christine LU (2003)
Abstract
Status epilepticus (SE) leads to neurodegeneration as well as neurogenesis in the adult rat hippocampus. This thesis demonstrates that even if the neurogenic response initially is very pronounced, with a several-fold increase in cell proliferation, the survival of the newly formed neurons is compromised by a death mechanism involving mitochondria-related caspases. This conclusion is based on immunohistochemical findings, as well as observations of increased number of newly generated neurons following intracerebroventricular infusions of caspase inhibitors in rats exposed to SE. We did not find any evidence for the involvement of two other cysteine protease families, the calpains and the cathepsins, and no expression of an active... (More)
Status epilepticus (SE) leads to neurodegeneration as well as neurogenesis in the adult rat hippocampus. This thesis demonstrates that even if the neurogenic response initially is very pronounced, with a several-fold increase in cell proliferation, the survival of the newly formed neurons is compromised by a death mechanism involving mitochondria-related caspases. This conclusion is based on immunohistochemical findings, as well as observations of increased number of newly generated neurons following intracerebroventricular infusions of caspase inhibitors in rats exposed to SE. We did not find any evidence for the involvement of two other cysteine protease families, the calpains and the cathepsins, and no expression of an active death-receptor-related cell death pathway. The survival of the new neurons depends upon the severity of the SE, since rats with a more severe, generalized form of SE have the same proliferative response but fewer surviving, newly formed neurons as compared to rats with a milder, partial form of SE. Recurrent seizures after the initial SE insult only seem to play a minor role for survival. Rats that had received additional seizures after their initial SE insult had the same survival rate and expression of cell death markers as rats without additional seizures. In the pathological environment emerging after SE, microglia activation plays an important part in impairing the survival of the newly generated neurons. When minocycline, an inhibitor of microglia activation, was administered to rats exposed to SE, the survival of the newborn neurons increased. Conversely, when lipopolysaccharide, an inducer of microglia activation, was intracortically infused into rats exposed to SE, the survival of the new neurons decreased. None of these treatments changed the magnitude of seizure-induced degeneration of neighboring mature neurons. In summary, we have characterized a caspase-mediated death pathway in newly generated neurons born after SE. We have also found that the seizure-induced activation of microglia is detrimental for the survival of the newly formed neurons. These findings are important for further investigations on the functional role of neurogenesis in epilepsy, as well as for neuroreplacement strategies with an aim to compensate for neuronal loss following neurodegenerative diseases, including epilepsy. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Dr Palmer, Theo, Stanford University
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Neurology, neuropsychology, neurophysiology, Neurologi, neuropsykologi, neurofysiologi, minocycline, lipopolysaccharide, microglia activation, status epilepticus, epilepsy, cysteinyl aspartate-specific proteases, apoptosis, neurogenesis, progenitor cell progeny
pages
142 pages
publisher
Christine Ekdahl Clementson; christine.ekdahl@neurol.lu.se,
defense location
Segerfalksalen WNC
defense date
2003-06-13 09:15
ISBN
91-628-5728-2
language
English
LU publication?
yes
id
977c8390-83cb-4697-ac59-0b869b36b612 (old id 465874)
date added to LUP
2007-09-11 12:12:10
date last changed
2016-09-19 08:45:13
@misc{977c8390-83cb-4697-ac59-0b869b36b612,
  abstract     = {Status epilepticus (SE) leads to neurodegeneration as well as neurogenesis in the adult rat hippocampus. This thesis demonstrates that even if the neurogenic response initially is very pronounced, with a several-fold increase in cell proliferation, the survival of the newly formed neurons is compromised by a death mechanism involving mitochondria-related caspases. This conclusion is based on immunohistochemical findings, as well as observations of increased number of newly generated neurons following intracerebroventricular infusions of caspase inhibitors in rats exposed to SE. We did not find any evidence for the involvement of two other cysteine protease families, the calpains and the cathepsins, and no expression of an active death-receptor-related cell death pathway. The survival of the new neurons depends upon the severity of the SE, since rats with a more severe, generalized form of SE have the same proliferative response but fewer surviving, newly formed neurons as compared to rats with a milder, partial form of SE. Recurrent seizures after the initial SE insult only seem to play a minor role for survival. Rats that had received additional seizures after their initial SE insult had the same survival rate and expression of cell death markers as rats without additional seizures. In the pathological environment emerging after SE, microglia activation plays an important part in impairing the survival of the newly generated neurons. When minocycline, an inhibitor of microglia activation, was administered to rats exposed to SE, the survival of the newborn neurons increased. Conversely, when lipopolysaccharide, an inducer of microglia activation, was intracortically infused into rats exposed to SE, the survival of the new neurons decreased. None of these treatments changed the magnitude of seizure-induced degeneration of neighboring mature neurons. In summary, we have characterized a caspase-mediated death pathway in newly generated neurons born after SE. We have also found that the seizure-induced activation of microglia is detrimental for the survival of the newly formed neurons. These findings are important for further investigations on the functional role of neurogenesis in epilepsy, as well as for neuroreplacement strategies with an aim to compensate for neuronal loss following neurodegenerative diseases, including epilepsy.},
  author       = {Ekdahl Clementson, Christine},
  isbn         = {91-628-5728-2},
  keyword      = {Neurology,neuropsychology,neurophysiology,Neurologi,neuropsykologi,neurofysiologi,minocycline,lipopolysaccharide,microglia activation,status epilepticus,epilepsy,cysteinyl aspartate-specific proteases,apoptosis,neurogenesis,progenitor cell progeny},
  language     = {eng},
  pages        = {142},
  publisher    = {ARRAY(0xb88bac8)},
  title        = {Death mechanisms compromising hippocampal neurogenesis after status epilepticus},
  year         = {2003},
}