Zinc transporter 3 modulates cell proliferation and neuronal differentiation in the adult hippocampus

Abstract

The subgranular zone of the dentate gyrus is a subregion of the hippocampus that has two uniquely defining features; it is one of the most active sites of adult neurogenesis as well as the location where the highest concentrations of synaptic zinc are found, the mossy fiber terminals. Therefore, we sought to investigate the idea that vesicular zinc plays a role as a modulator of hippocampal adult neurogenesis. Here, we used ZnT3 −/− mice, which are depleted of synaptic-vesicle zinc, to test the effect of targeted deletion of this transporter on adult neurogenesis. We found that this manipulation reduced progenitor cell turnover as well as led to a marked defect in the maturation of newborn cells that survive in the DG toward a neuronal phenotype. We also investigated the effects of zinc (ZnCl 2), n-acetyl cysteine (NAC), and ZnCl 2 plus 2NAC (ZN) supplement on adult hippocampal neurogenesis. Compared with ZnCl 2 or NAC, administration of ZN resulted in an increase in proliferation of progenitor cells and neuroblast. ZN also rescued the ZnT3 loss-associated reduction of neurogenesis via elevation of insulin-like growth factor-1 and ERK/CREB activation. Together, these findings reveal that ZnT3 plays a highly important role in maintaining adult hippocampal neurogenesis and supplementation by ZN has a beneficial effect on hippocampal neurogenesis, as well as providing a therapeutic target for enhanced neuroprotection and repair after injury as demonstrated by its ability to prevent aging-dependent cognitive decline in ZnT3 −/− mice. Therefore, the present study suggests that ZnT3 and vesicular zinc are essential for adult hippocampal neurogenesis.

Zinc deficiency as a possible risk factor for increased susceptibility and severe progression of Corona Virus Disease 19

“…In addition, Zn functions as an important neuromodulator in the olfactory bulbs in rodents (240,241) . Restricting the release of Zn by knocking out the Zn exporter ZnT3 inhibited cell proliferation and neuronal differentiation in the adult hippocampus in mice (242) . Surprisingly, Zn in the brain remains unaltered or might even be elevated and involved in Alzheimer-related plaque formation in Zn-deficient animals and humans (243)(244)(245) .…”

Zinc in the Brain: Friend or Foe?

“…Our laboratory has demonstrated that synaptic zinc is an important factor for modulating hippocampal neurogenesis, and we used ZnT3 knockout mice to address this question. ZnT3 deficiency reduced progenitor cell proliferation and neuronal differentiation in the hippocampus, which was mediated by decreasing levels of IGF-1, ERK1/2 phosphorylation, and cyclic AMP response element binding protein (CREB) in the hippocampus of ZnT3 knockout mice at three months of age [ 70 ].…”

Transient Receptor Potential Melastatin 2 (TRPM2) Inhibition by Antioxidant, N-Acetyl-l-Cysteine, Reduces Global Cerebral Ischemia-Induced Neuronal Death

“…In the pre-synaptic vesicles, chelatable zinc is abundant. It is released into the synaptic cleft, moved into pre-synaptic neurons via several transporters, and subsequently undergoes reuptake from the synaptic cleft under normal physiological conditions [ 22 , 23 ]. Under abnormal physiological conditions, such as neurological disorders, zinc homeostasis is disturbed and dysregulated.…”