Seizures increase cell proliferation in the dentate gyrus by shortening progenitor cell-cycle length.
OBJECTIVE
A prolonged seizure, status epileptics (SE), is a potent stimulus for increased neurogenesis in the dentate gyrus of the hippocampus. Molecular mechanisms that regulate normal and pathologic cell birth in the dentate gyrus are poorly understood.


METHODS
Lithium-pilocarpine was used to induce SE in immature postnatal day 20 rats. Newborn cells in the dentate were labeled with bromo-deoxyuridine to determine a time-course of cell proliferation, and measure cell-cycle length. In addition, we studied expression by Western blot and immunohistochemistry of two known inhibitors of G(1)-S cell-cycle progression P27/Kip1 and P15/Ink4b following SE.


RESULTS
Cell proliferation in the dentate gyrus increases starting 2 h after SE and is sustained for 40 days. Increased cell proliferation following SE is associated with a shortened dentate gyrus progenitor's cell cycle, 15 h in control to 12 h in the SE animals. To identify molecules responsible for the shortened progenitor cell cycle we studied inhibitors of cell-cycle progression P27/Kip1, and P15/Ink4b. We find decreased phosphorylation at P27/Kip1 Serine 10 and Threonine 187 following SE. Although total P27/Kip1 and P15/Ink4b levels were not altered after SE, P27/Kip1 immunoreactivity was minimal in newborn but increased with maturation of the dentate granule neurons.


CONCLUSIONS
The sustained increase in dentate gyrus cell proliferation following SE provides a large pool of immature dentate granule cells prior to development of spontaneous seizures. A decrease in cell-cycle length of dentate gyrus progenitors is at least partially responsible for increased numbers of newborn cells following SE.
Varodayan
Florence P
FP
Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Zhu
Xin-Jian
XJ
Cui
Xiao-Nan
XN
Porter
Brenda E
BE
D000818:Animals; D000831:Animals, Newborn; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation; D018891:Dentate Gyrus / Q000502:physiology*; D006624:Hippocampus; D006801:Humans; D007150:Immunohistochemistry; D008094:Lithium; D009474:Neurons; D010862:Pilocarpine; D013226:Status Epilepticus / Q000503:physiopathology*; D013234:Stem Cells / Q000502:physiology
D010862:Pilocarpine; D008094:Lithium