Abstract
Acute Seizure (AS) activity in young adult age conspicuously modifies hippocampal neurogenesis. This is epitomized by both increased addition of new neurons to the granule cell layer (GCL) by neural stem/progenitor cells (NSCs) in the dentate subgranular zone (SGZ), and greatly enhanced numbers of newly born neurons located abnormally in the dentate hilus (DH). Interestingly, AS activity in old age does not induce such changes in hippocampal neurogenesis. However, the effect of AS activity on neurogenesis in the middle-aged hippocampus is yet to be elucidated. We examined hippocampal neurogenesis in middle-aged F344 rats after a continuous AS activity for >4 hrs, induced through graded intraperitoneal injections of the kainic acid. We labeled newly born cells via daily intraperitoneal injections of the 5′-bromodeoxyuridine (BrdU) for 12 days, commencing from the day of induction of AS activity. AS activity enhanced the addition of newly born BrdU+ cells by 5.6 fold and newly born neurons (expressing both BrdU and doublecortin [DCX]) by 2.2 fold to the SGZ-GCL. Measurement of the total number of DCX+ newly born neurons also revealed a similar trend. Furthermore, AS activity increased DCX+ newly born neurons located ectopically in the DH (2.7 fold increase and 17% of total newly born neurons). This rate of ectopic migration is however considerably less than what was observed earlier for the young adult hippocampus after similar AS activity. Thus, the plasticity of hippocampal neurogenesis to AS activity in middle age is closer to its response observed in the young adult age. However, the extent of abnormal migration of newly born neurons into the DH is less than that of the young adult hippocampus after similar AS activity. These results also point out a highly divergent response of neurogenesis to AS activity between middle age and old age.
Highlights
Production of new neurons through proliferation of neural stem/ progenitor cells (NSCs) and neuronal differentiation of newly born cells occurs all through life in the hippocampus of most mammals [1,2,3,4]
Acute seizure activity was induced in middle-aged (12-months old) F344 rats through 2–4 graded intraperitoneal injections of the excitotoxin kainic acid (KA) (3 mg/Kg body weight [b.w.]/hour)
The dentate granule cell layer did not display any apparent loss of neurons (Fig. 1 [B1, B2])
Summary
Production of new neurons through proliferation of neural stem/ progenitor cells (NSCs) and neuronal differentiation of newly born cells occurs all through life in the hippocampus of most mammals [1,2,3,4]. The extent of hippocampal neurogenesis varies conspicuously in response to alterations in the dentate gyrus (DG) microenvironment. Increased levels of NSC mitogenic factors (such as fibroblast growth factor-2 [FGF-2], brain-derived neurotrophic factor [BDNF], insulin-like growth factor-1 [IGF-1] and vascular endothelial growth factor [VEGF]), enhanced physical activity, caloric restriction, environmental enrichment, and increased neural activity considerably enhance the extent of hippocampal neurogenesis [13,14,15,16,17,18,19,20,21,22,23,24,25]. Aging is a negative regulator of hippocampal neurogenesis, which is typified by an increased quiescence of NSCs likely due to age-related adverse changes in their microenvironment ([26,27,28,29,30]; see [31]). The DG microenvironment appears to be one of the major factors that regulate the extent of hippocampal neurogenesis
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