Decreased neuronal differentiation of newly generated cells underlies reduced hippocampal neurogenesis in chronic temporal lobe epilepsy

Abstract

Hippocampal neurogenesis declines substantially in chronic temporal lobe epilepsy (TLE). However, it is unclear whether this decline is linked to altered production of new cells and/or diminished survival and neuronal fate-choice decision of newly born cells. We quantified different components of hippocampal neurogenesis in rats exhibiting chronic TLE. Through intraperitoneal administration of 5′-bromodeoxyuridine (BrdU) for 12 days, we measured numbers of newly born cells in the subgranular zone-granule cell layer (SGZ-GCL) at 24 h and 2.5 months post-BrdU administration. Furthermore, the differentiation of newly added cells into neurons and glia was quantified via dual immunofluorescence for BrdU and various markers of neurons and glia. Addition of new cells to the SGZ-GCL over 12 days was comparable between the chronically epileptic hippocampus and the age-matched intact hippocampus. Furthermore, comparison of BrdU+ cells measured at 24 h and 2.5 months post-BrdU administration revealed similar survival of newly born cells between the two groups. However, only 4-5% of newly born cells (i.e., BrdU+ cells) differentiated into neurons in the chronically epileptic hippocampus, in comparison to 73-80% of such cells exhibiting neuronal differentiation in the intact hippocampus. Moreover, differentiation of newly born cells into S-100β+ astrocytes or NG2+ oligodendrocyte progenitors increased to ̃79% in the chronically epileptic hippocampus from ̃25% observed in the intact hippocampus. Interestingly, the extent of proliferation of astrocytes and microglia (identified through Ki-67 and S-100b and Ki-67 and OX-42 dual immunofluorescence) in the SGZ-GCL was similar between the chronically epileptic hippocampus and the age-matched intact hippocampus, implying that the proliferation of neural stem/progenitor cells in the SGZ-GCL of the chronically epileptic hippocampus was not obscured by an increased division of glia. Thus, severely diminished DG neurogenesis in chronic TLE is not associated with either decreased production of new cells or reduced survival of newly born cells in the SGZ-GCL. Rather, it is linked to a dramatic decline in the neuronal fate-choice decision of newly generated cells. Overall, the differentiation of newly born cells turns mainly into glia with chronic TLE from predominantly neuronal differentiation seen in control conditions. © 2009 Wiley-Liss, Inc.