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.
Department of Neurology, University of California Los Angeles School of Medicine, Los Angeles, California 90095-1752, USA.
R
R
Sankar
D H
DH
Shin
H
H
Liu
A
A
Mazarati
A
A
Pereira de Vasconcelos
C G
CG
Wasterlain
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