Blockade of L‐type voltage‐gated Ca2+ channel inhibits ischemia‐induced neurogenesis by down‐regulating iNOS expression in adult mouse
Chun Xia LuoXin ZhuAi Xia ZhangWei WangXiao YangShu Hong LiuXiao HanJin SunShu Gang ZhangYouming LuDong Ya Zhu
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Abstract Neurogenesis in the adult mammalian hippocampus may contribute to repairing the brain after injury. The signals that regulate neurogenesis in the dentate gyrus following ischemic stroke insult are not well known. We have previously reported that inducible nitric oxide synthase (iNOS) expression is necessary for ischemia‐stimulated neurogenesis in the adult dentate gyrus. Here, we show that mice subjected to 90 min of middle cerebral artery occlusion (MCAO) significantly increased the number of new neurons and up‐regulated iNOS expression in the dentate gyrus. Blockade of the L‐type voltage‐gated Ca 2+ channel (L‐VGCC) prevented neurogenesis in the dentate gyrus and subventricular zone (SVZ), and down‐regulated iNOS expression in the dentate gyrus after cerebral ischemia. This study suggests that Ca 2+ influx through L‐VGCC is involved in ischemia‐induced neurogenesis by up‐regulating iNOS expression.Although the existence of adult neurogenesis in the dentate gyrus is now almost universally accepted, it is not widely established that the new neurons perform any necessary function. However, evidence indicates that the number of new neurons that are generated and form functional synapses is clearly large enough to impact the circuitry of the hippocampus. Additionally, several treatments show parallel effects on neurogenesis and hippocampus-dependent behaviors, suggesting a possible causal relationship between new neurons and hippocampal function. Most importantly, several recent studies have found that killing or inhibiting proliferation of granule cell precursors impairs performance on several hippocampus-dependent tasks. Control experiments showing no impairment on slightly different behavioral tests suggest that the deficits are highly specific and unlikely to result from side effects of the neurogenesis-inhibiting treatments. In summary, the evidence to date strongly suggests that adult neurogenesis in the dentate gyrus plays a vital role in hippocampal function.
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Adult neurogenesis occurs in two major niches in the brain: the subgranular zone of the hippocampal formation and the ventricular-subventricular zone. Neurogenesis in both niches is reduced in ageing and neurological disease involving dementia. Exercise can rescue memory by enhancing hippocampal neurogenesis, but whether exercise affects adult neurogenesis in the ventricular-subventricular zone remains unresolved. Previously, we reported that exercise induces angiogenesis through activation of the lactate receptor HCA1. The aim of the present study is to investigate HCA1 -dependent effects on neurogenesis in the two main neurogenic niches.Wild-type and HCA1 knock-out mice received high intensity interval exercise, subcutaneous injections of L-lactate, or saline injections, five days per week for seven weeks. Well-established markers for proliferating cells (Ki-67) and immature neurons (doublecortin), were used to investigate neurogenesis in the subgranular zone and the ventricular-subventricular zone.We demonstrated that neurogenesis in the ventricular-subventricular zone is enhanced by HCA1 activation: Treatment with exercise or lactate resulted in increased neurogenesis in wild-type, but not in HCA1 knock-out mice. In the subgranular zone, neurogenesis was induced by exercise in both genotypes, but unaffected by lactate treatment.Our study demonstrates that neurogenesis in the two main neurogenic niches in the brain is regulated differently: Neurogenesis in both niches was induced by exercise, but only in the ventricular-subventricular zone was neurogenesis induced by lactate through HCA1 activation. This opens for a role of HCA1 in the physiological control of neurogenesis, and potentially in counteracting age-related cognitive decline.
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Abstract The dentate gyrus continues to produce new neurons in adult rodents. The possibility of differential regulation of neurogenesis within regions of the dentate gyrus is largely unexplored, despite several other aspects of this phenomenon being well characterized in a large number of studies. In this report, we describe an area located at the anterior pole of the dentate gyrus that consistently lacks neurogenesis. This neurogenically quiescent zone invariably lacks expression of the neuroblast marker doublecortin (DCX), bromodeoxyuridine and Ki‐67, though DCX expression can be elicited in response to a combined paradigm of environmental enrichment and wheel running. We propose that this region may provide a valuable model system to discern the factors that regulate the process of neurogenesis.
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