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Copper Modulates Adult Neurogenesis in Brain Subventricular Zone

School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, West Lafayette, IN 47907, USA
Author to whom correspondence should be addressed.
Academic Editor: Lothar Rink
Int. J. Mol. Sci. 2022, 23(17), 9888;
Received: 8 August 2022 / Revised: 25 August 2022 / Accepted: 26 August 2022 / Published: 31 August 2022
(This article belongs to the Special Issue Current Topics in Trace Element and Mineral Research)
The subventricular zone (SVZ) in lateral ventricles is the largest neurogenic region in adult brain containing high amounts of copper (Cu). This study aims to define the role of Cu in adult neurogenesis by chelating labile Cu ions using a well-established Cu chelator D-Penicillamine (D-Pen). A neurosphere model derived from adult mouse SVZ tissues was established and characterized for its functionality with regards to neural stem/progenitor cells (NSPCs). Applying D-Pen in cultured neurospheres significantly reduced intracellular Cu levels and reversed the Cu-induced suppression of NSPC’s differentiation and migration. An in vivo intracerebroventricular (ICV) infusion model was subsequently established to infuse D-Pen directly into the lateral ventricle. Metal analyses revealed a selective reduction of Cu in SVZ by 13.1% (p = 0.19) and 21.4% (p < 0.05) following D-Pen infusions at low (0.075 μg/h) and high (0.75 μg/h) doses for 28 days, respectively, compared to saline-infused controls. Immunohistochemical studies revealed that the 7-day, low-dose D-Pen infusion significantly increased Ki67(+)/Nestin(+) cell counts in SVZ by 28% (p < 0.05). Quantification of BrdU(+)/doublecortin (DCX)(+) newborn neuroblasts in the rostral migration stream (RMS) and olfactory bulb (OB) further revealed that the short-term, low-dose D-Pen infusion, as compared with saline-infused controls, resulted in more newborn neuroblasts in OB, while the high-dose D-Pen infusion showed fewer newborn neuroblasts in OB but with more arrested in the RMS. Long-term (28-day) infusion revealed similar outcomes. The qPCR data from neurosphere experiments revealed altered expressions of mRNAs encoding key proteins known to regulate SVZ adult neurogenesis, including, but not limited to, Shh, Dlx2, and Slit1, in response to the changed Cu level in neurospheres. Further immunohistochemical data indicated that Cu chelation also altered the expression of high-affinity copper uptake protein 1 (CTR1) and metallothionein-3 (MT3) in the SVZ as well as CTR1 in the choroid plexus, a tissue regulating brain Cu homeostasis. Taken together, this study provides first-hand evidence that a high Cu level in SVZ appears likely to maintain the stability of adult neurogenesis in this neurogenic zone. View Full-Text
Keywords: copper; subventricular zone; adult neurogenesis; neurosphere; D-penicillamine; intracerebroventricular infusion copper; subventricular zone; adult neurogenesis; neurosphere; D-penicillamine; intracerebroventricular infusion
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MDPI and ACS Style

Liu, L.L.; van Rijn, R.M.; Zheng, W. Copper Modulates Adult Neurogenesis in Brain Subventricular Zone. Int. J. Mol. Sci. 2022, 23, 9888.

AMA Style

Liu LL, van Rijn RM, Zheng W. Copper Modulates Adult Neurogenesis in Brain Subventricular Zone. International Journal of Molecular Sciences. 2022; 23(17):9888.

Chicago/Turabian Style

Liu, Luke L., Richard M. van Rijn, and Wei Zheng. 2022. "Copper Modulates Adult Neurogenesis in Brain Subventricular Zone" International Journal of Molecular Sciences 23, no. 17: 9888.

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