Seizures Decrease Postnatal Neurogenesis and Granule Cell Development in the Human Fascia Dentata *Gary W. Mathern, *James L. Leiphart, *Adelaine De Vera, †P. David Adelson, ‡Tatsunori Seki, §Luciano Neder, and §Joao P. Leite *Division of Neurosurgery, The Mental Retardation Research Center, and The Brain Research Institute, University of California, Los Angeles, Los Angeles, California, and †Department of Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.; ‡Department of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and §Departments of Neurology and Pathology, Ribeira ˜o Preto School of Medicine, University of Sa ˜o Paulo, Ribeira ˜ o Preto, Brazil Summary: Purpose: There is considerable controversy whether childhood seizures damage existing neurons and/or adversely affect neurogenesis and synaptogenesis. This study addressed this question by examining fascia dentata neurogen- esis, cell death, and aberrant axon connections in hippocampi from children with extratemporal seizure foci. Methods: Surgically resected (n  53) and age-comparable autopsy (n  22) hippocampi were studied for neuronal den- sities, polysialic acid (PSA) neural cell adhesion molecule (NCAM) immunoreactivity (IR), TUNEL, and neo-Timm’s histochemistry. Results: Compared with autopsy cases, hippocampi from children with frequent seizures showed (a) decreased fascia dentata granule cell densities; (b) decreased PSA NCAM IR cell densities in the stratum granulosum, infragranular, and hi- lar regions; (c) no positive TUNEL-stained cells; and (d) ab- errant supragranular mossy fiber axon connections. Conclusions: These results indicate that severe seizures dur- ing early childhood are associated with anatomic signs of de- creased postnatal granule cell neurogenesis (PSA NCAM IR) and aberrant mossy fiber axon connections (neo-Timm’s) with- out evidence of seizure-induced cell death (TUNEL). In hu- mans, these results support the concept that seizures do not damage existing neurons, but adversely affect processes in- volved with normal postnatal neuronal development such as neurogenesis and axon formation. Such alterations probably negatively affect normal brain development, and/or promote epileptogenesis. Key Words: Hippocampus—Mossy fibers— Synaptogenesis—Epilepsy. The effects of seizures in the developing brain differ compared with those in the mature brain. In adult ani- mals, frequent seizures and/or status epilepticus result in neuronal loss, aberrant axon sprouting, and long-term deficits in learning, memory, and behavior (1,2). Similar experiments in immature rats demonstrate minimal or no pathology unless the brain insults are severe, and even then, the amount of damage is generally less than with the same insult in adult rats (3–5). Some authors have concluded, therefore, that the immature brain is resistant to seizure-induced neuronal damage. However, these ex- periments do not address whether seizures adversely af- fect other developmental processes, such as postnatal neurogenesis, axogenesis, and synaptogenesis, which are equally important components of early brain develop- ment. Previous animal studies demonstrated that neonatal seizures may adversely affect some aspects of brain de- velopment, and in adult rats, reported increased postsei- zure neurogenesis of fascia dentata granule cells (6–10). Another study, however, showed that granule cell neu- rogenesis was reduced in postnatal (PN) day 1–4 rats with repeated flurothyl-induced seizures (11). Hence, it is unclear if seizures during early hippocampal develop- ment might alter postnatal granule cell neurogenesis, and whether this is associated with aberrant mossy fiber sprouting. Previous human studies from our laboratory found decreased granule cell densities in young patients with extratemporal seizures (12,13). Whether decreased granule cell densities began early in life or were the consequence of repeated seizures over time was unclear because of the small sample size. Likewise, it was un- known if decreased granule cell numbers were from re- duced neurogenesis or seizure-induced cell death of already formed granule cells. The current human study addresses these questions by performing immunocyto- chemistry (ICC) for polysialic acid (PSA) neural cell Address correspondence and reprint requests to Dr. G.W. Mathern at Division of Neurosurgery, Reed Neurological Research Center, 710 Westwood Plaza, Room 2123, Los Angeles, CA 90095-1769, U.S.A. E-mail: gmathern@ucla.edu Epilepsia, 43(Suppl. 5):68–73, 2002 Blackwell Publishing, Inc. © International League Against Epilepsy 68