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The Journal of Neuroscience, February 21, 2007, 27(8):1803-1811; doi:10.1523/JNEUROSCI.3111-06.2007

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Neurobiology of Disease
Reelin Regulates Neuronal Progenitor Migration in Intact and Epileptic Hippocampus

Chao Gong, ^* Tsu-Wei Wang, ^* Holly S. Huang, and Jack M. Parent

Department of Neurology and Program for Neuroscience, University of Michigan Medical Center, Ann Arbor, Michigan 48109

Correspondence should be addressed to Dr. Jack M. Parent, University of Michigan Medical Center, 109 Zina Pitcher Place, 5021 Biomedical Science Research Building, Ann Arbor, MI 48109-2200. Email: parent{at}umich.edu

Dentate granule cell (DGC) neurogenesis persists throughout life in the mammalian hippocampal dentate gyrus and increases after epileptogenic insults. The DGC layer in human and experimental mesial temporal lobe epilepsy (mTLE) often shows abnormal dispersion and the appearance of hilar-ectopic DGCs. In the pilocarpine mTLE model, hilar-ectopic DGCs arise as a result of an aberrant chain migration of neural progenitors. Reelin is a secreted migration guidance cue that persists in the adult rodent and human hippocampus. We tested the hypothesis that loss of Reelin in the epileptic dentate gyrus leads to aberrant chain migration of DGC precursors. We found that interneuron subsets typically lost in human and experimental mTLE express Reelin, and DGC progenitors express the downstream Reelin signaling molecule Disabled 1 (Dab1). Prolonged seizures decreased Reelin immunoreactivity in the adult rat dentate gyrus and increased Dab1 expression in hilar-ectopic neuroblasts. Exogenous Reelin increased detachment of chain-migrating neuroblasts in dentate gyrus explants, and blockade of Reelin signaling increased chain migration. These findings suggest that Reelin modulates DGC progenitor migration to maintain normal DGC integration in the neonatal and adult mammalian dentate gyrus. Loss of Reelin expression in the epileptic adult hippocampus, moreover, likely contributes to ectopic chain migration and aberrant integration of newborn DGCs.

Key words: neurogenesis; neuronal migration; Reelin; neural stem cell; epileptogenesis; hippocampus

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Received July 21, 2006; revised Nov. 28, 2006; accepted Jan. 8, 2007.

Correspondence should be addressed to Dr. Jack M. Parent, University of Michigan Medical Center, 109 Zina Pitcher Place, 5021 Biomedical Science Research Building, Ann Arbor, MI 48109-2200. Email: parent{at}umich.edu

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