Patterns of status epilepticus-induced neuronal injury during development and long-term consequences.
The lithium-pilocarpine model of status epilepticus (SE) was used to study the type and distribution of seizure-induced neuronal injury in the rat and its consequences during development. Cell death was evaluated in hematoxylin- and eosin-stained sections and by electron microscopy. Damage to the CA1 neurons was maximal in the 2- and 3-week-old pups and decreased as a function of age. On the other hand, damage to the hilar and CA3 neurons was minimal in the 2-week-old rat pups but reached an adult-like pattern in the 3-week-old animals, and damage to amygdalar neurons increased progressively with age. The 3-week-old animals also demonstrated vulnerability of the dentate granule cells. To evaluate neuronal apoptosis, we used terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) stain, confocal fluorescence microscopy of ethidium bromide-stained sections, electron microscopy, and DNA electrophoresis. Neurons displaying all of those features of apoptotic death in response to SE were seen in the CA1 region of the 2-week-old pups and in the hilar border of the dentate granule cells of the 3-week-old animals. Some (3/11) of the animals that underwent SE at 2 weeks of age and most of the animals that underwent SE at 3 or 4 weeks of age (8/11 and 6/8, respectively) developed spontaneous seizures later in life; the latter showed SE-induced synaptic reorganization as demonstrated by Timm methodology. These results provide strong evidence for the vulnerability of the immature brain to seizure-induced damage, which bears features of both necrotic and apoptotic death and contributes to synaptic reorganization and the development of chronic epilepsy.
Sankar
R
R
Department of Neurology, University of California Los Angeles School of Medicine, Los Angeles, California 90095-1752, USA.
Shin
D H
DH
Liu
H
H
Mazarati
A
A
Pereira de Vasconcelos
A
A
Wasterlain
C G
CG
D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001522:Behavior, Animal / Q000502:physiology; D004247:DNA / Q000032:analysis; D004569:Electroencephalography; D005260:Female; D020287:In Situ Nick-End Labeling; D008094:Lithium; D008297:Male; D008854:Microscopy, Electron; D019599:Mossy Fibers, Hippocampal / Q000254:growth & development* / Q000502:physiology / Q000648:ultrastructure; D018721:Muscarinic Agonists; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D010862:Pilocarpine; D051381:Rats; D017208:Rats, Wistar; D013226:Status Epilepticus / Q000139:chemically induced / Q000503:physiopathology*; D013569:Synapses / Q000502:physiology / Q000648:ultrastructure
D018721:Muscarinic Agonists; D010862:Pilocarpine; D004247:DNA; D008094:Lithium