Abstract
Several studies have demonstrated that excitatory amino acid carrier-1 (EAAC1) gene deletion exacerbates hippocampal and cortical neuronal death after ischemia. However, presently there are no studies investigating the role of EAAC1 in hippocampal neurogenesis. In this study, we tested the hypothesis that reduced cysteine transport into neurons by EAAC1 knockout negatively affects adult hippocampal neurogenesis under physiological or pathological states. This study used young mice (aged 3–5 months) and aged mice (aged 11–15 months) of either the wild-type (WT) or EAAC1−/− genotype. Ischemia was induced through the occlusion of bilateral common carotid arteries for 30 minutes. Histological analysis was performed at 7 or 30 days after ischemia. We found that both young and aged mice with loss of the EAAC1 displayed unaltered cell proliferation and neuronal differentiation, as compared to age-matched WT mice under ischemia-free conditions. However, neurons generated from EAAC1−/− mice showed poor survival outcomes in both young and aged mice. In addition, deletion of EAAC1 reduced the overall level of neurogenesis, including cell proliferation, differentiation, and survival after ischemia. The present study demonstrates that EAAC1 is important for the survival of newly generated neurons in the adult brain under physiological and pathological conditions. Therefore, this study suggests that EAAC1 plays an essential role in modulating hippocampal neurogenesis.
Highlights
Adult hippocampal neurogenesis, which originates in neural progenitor cells (NPCs), occurs continuously in the subgranular zone (SGZ) of the dentate gyrus (DG)
excitatory amino acid carrier-1 (EAAC1) is highly expressed in neurons of the central nervous system (CNS)[16]
We investigated whether the decrease in ischemia-induced progenitor cell proliferation in the SGZ, caused by gene deletion of EAAC1, gave rise to reduced neuroblast production
Summary
Adult hippocampal neurogenesis, which originates in neural progenitor cells (NPCs), occurs continuously in the subgranular zone (SGZ) of the dentate gyrus (DG). One key mechanism underlying impaired neurogenesis in aging, stroke, or traumatic brain injury is increased oxidative stress, which serves as a major obstacle for neuronal proliferation, differentiation, and survival. The presence of an endogenous cellular defense mechanism against oxidative stress in the above neurogenesis processes has been suggested, and may occur via the enhanced production of endogenous antioxidant molecules. Glutathione, one such molecule, is known to play an important role in maintaining cellular antioxidant function[5]. Our previous study has demonstrated that N-acetyl cysteine (NAC), a membrane-permeant cysteine prodrug, increases basal GSH levels in EAAC1−/− mice and reduces ischemic neuronal death[15]. Histological evaluation for neurogenesis was performed at 7 or 30 days after ischemia was induced
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