The Journal of Neuroscience, March 1, 2003, 23(5):1742
Hippocampal Neurogenesis Follows Kainic Acid-Induced Apoptosis in
Neonatal Rats
Hongxin
Dong1,
Cynthia
A.
Csernansky1,
Brian
Goico1, and
John G.
Csernansky1, 2
Departments of 1 Psychiatry and 2 Anatomy
and Neurobiology, Washington University School of Medicine, St. Louis,
Missouri 63110
The effects of kainic acid (KA) on neurogenesis in the developing
rat hippocampus were investigated. Neonatal [postnatal day (P) 7]
rats received a single bilateral intracerebroventricular infusion of KA
(50 nmol in 1.0 µl) or vehicle. At P14, P25, P40, and P60, the
spatial and temporal relationships between the neurodegeneration and
neurogenesis induced by KA were explored using terminal
deoxynucleotidyl transferase-mediated biotinylated UTP nick end
labeling (TUNEL) to detect the dying cells and 5-bromodeoxyuridine
(BrdU) to label newly generated cells.
There was progressive loss of neurons in the cornu ammonis (CA)
1 and CA3 subfields of the hippocampus at all time points in KA-treated
rats. TUNEL staining identified dying cells at P14 through P60, mainly
in the CA3 subfield. The number of TUNEL-positive cells decreased with
age. Neurogenesis also was observed in the KA-treated hippocampus. The
number of BrdU-positive cells in the dentate gyrus was significantly
decreased at P14, when the number of TUNEL-positive cells is highest.
However, at later time points (P40 and P60) the number of BrdU-positive
cells in the dentate gyrus was significantly increased. In addition,
the number of BrdU-positive cells was increased in the CA3 subfield at
P40 and P60 in KA-treated rats. A substantial proportion (40%) of the newly generated cells in CA3 also expressed markers of immature and
mature neurons (class III
-tubulin and neuronal nuclei). Newly generated cells in the CA3 subfield only rarely expressed glial
markers (8%).
These results suggest that a single exposure to KA at P7 has both
immediate (inhibition) and delayed (stimulation) effects on
neurogenesis within the dentate gyrus of developing rats. KA administration resulted in both neuronal apoptosis and neurogenesis within the CA3 subfield, suggesting that the purpose of neurogenesis in
the CA3 is to replace neurons lost to apoptosis.
Key words:
neurogenesis; apoptosis; BrdU mitotic labeling; hippocampus; kainic acid; neurodevelopment; schizophrenia
Copyright © 2003 Society for Neuroscience 0270-6474/03/2351742-08$05.00/0