Abstract
Several studies have shown that epileptic seizures increase hippocampal neurogenesis in the adult. However, the mechanism underlying increased neurogenesis after seizures remains largely unknown. Neurogenesis occurs in the subgranular zone (SGZ) of the hippocampus in the adult brain, although an understanding of why it actively occurs in this region has remained elusive. A high level of vesicular zinc is localized in the presynaptic terminals of the SGZ. Previously, we demonstrated that a possible correlation may exist between synaptic zinc localization and high rates of neurogenesis in this area after hypoglycemia. Using a lithium-pilocarpine model, we tested our hypothesis that zinc plays a key role in modulating hippocampal neurogenesis after seizure. Then, we injected the zinc chelator, clioquinol (CQ, 30 mg/kg), into the intraperitoneal space to reduce brain zinc availability. Neuronal death was detected with Fluoro Jade-B and NeuN staining to determine whether CQ has neuroprotective effects after seizure. The total number of degenerating and live neurons was similar in vehicle and in CQ treated rats at 1 week after seizure. Neurogenesis was evaluated using BrdU, Ki67 and doublecortin (DCX) immunostaining 1 week after seizure. The number of BrdU, Ki67 and DCX positive cell was increased after seizure. However, the number of BrdU, Ki67 and DCX positive cells was significantly decreased by CQ treatment. Intracellular zinc chelator, N,N,N0,N-Tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), also reduced seizure-induced neurogenesis in the hippocampus. The present study shows that zinc chelation does not prevent neurodegeneration but does reduce seizure-induced progenitor cell proliferation and neurogenesis. Therefore, this study suggests that zinc has an essential role for modulating hippocampal neurogenesis after seizure.
Highlights
It is well known that seizure increases adult neurogenesis in the subgranular zones (SGZ) of dentate gyrus of hippocampus in both the rodent and human brain [1,2,3]
The present study tested the hypothesis that brain zinc might play a modulatory role in hippocampal neurogenesis either in normal or in epilepsy-experienced rats
This study found that pharmacological zinc chelation substantially reduced basal or seizure-induced progenitor cell proliferation
Summary
It is well known that seizure increases adult neurogenesis in the subgranular zones (SGZ) of dentate gyrus of hippocampus in both the rodent and human brain [1,2,3]. Newly-born dentate granule cells that arise as a result of seizure integrate into existing hippocampal circuitry and may provide network plasticity for hippocampus-dependent learning and memory. It is important to study how neurons are born in response to epileptic seizure and functionally integrated into the existing neural networks. Severe seizure induced a short-term increase in the proliferation of neural progenitors, but most of the new cells died at 4 weeks after insult. The exact mechanisms by which seizure regulates progenitor cell proliferation and neurogenesis are not well understood
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