Immediate and delayed hippocampal neuronal loss induced by kainic acid during early postnatal development in the rat.
The degree to which the neonatal hippocampus is resistant to the effects of excitotoxins, such as kainic acid (KA) remains uncertain. Previously, we showed delayed loss of hippocampal neurons during pubescence in neonatal rats subjected to intracerebroventricular (i.c.v.) KA administration (10 nmol) at postnatal day 7 (P7). To further characterize the time course as well as the underlying mechanisms of this neuronal loss, we administered i.c.v. KA (10 or 50 nmol) to P7 preweanling rats. Brain sections were then examined at several neurodevelopmental time points (i.e., P8, P14, P25, P40, P60 and P75) using thionin staining and three-dimensional, non-biased cell counting to assess neuronal loss, and immunohistochemistry and electron microscopy to search for evidence of necrosis and apoptosis. Dose-dependent acute neuronal loss was observed at P8-P14 in hippocampal subfields CA3a and CA3c. Transient heat shock protein (HSP-70) immunostaining accompanied this acute neuronal loss. Progressive neuronal loss then continued in CA3 until P75, but without concomitant HSP-70 immunostaining. Progressive neuronal cell loss was also observed in the CA1 subfield of the hippocampus beginning at pubescence (i.e., P40) and continuing until P75. The appearance of TUNEL-positive hippocampal neurons accompanied the delayed neuronal loss in both CA3 and CA1 and electron micrographs confirmed that neurons in these subfields were undergoing apoptosis. KA administration (i.c.v.) to preweanling rats caused both immediate and delayed damage to hippocampal neurons. The effect of KA was dose-dependent, and the delayed neuronal damage occurred through an apoptosis-mediated mechanism. These findings may be relevant to the pathogenesis of some neuropsychiatric disorders, where early CNS injury is not apparent until the onset of clinical symptoms in young adulthood.
Department of Psychiatry, Washington University School of Medicine, Campus Box 8134, 660 South Euclid Ave., St. Louis, MO 63110, USA.
William M
WM
Humphrey
HongXin
H
Dong
Cynthia A
CA
Csernansky
John G
JG
Csernansky
D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers; D002452:Cell Count; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005260:Female; D006624:Hippocampus / Q000166:cytology* / Q000196:embryology*; D020287:In Situ Nick-End Labeling; D007608:Kainic Acid / Q000494:pharmacology*; D008854:Microscopy, Electron; D008867:Microtomy; D017966:Pyramidal Cells / Q000187:drug effects / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000473:pathology
D015415:Biomarkers; D018690:Excitatory Amino Acid Agonists; D007608:Kainic Acid