Brain‐derived neurotrophic factor but not vesicular zinc promotes TrkB activation within mossy fibers of mouse hippocampus in vivo

Helgager, Jeffrey; Huang, Yang; McNamara, James O

doi:10.1002/cne.23647

Cited by 28 publications

(27 citation statements)

References 50 publications

(108 reference statements)

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“…Hence, although BDNF may be upregulated throughout the forebrain, its specific pattern of expression may differ between brain regions. Although the precise mechanism for BDNF upregulation in ZnT3 null mice is unknown, this finding is consistent with the report by Helgager that showed increased BDNF levels in relatively young ZnT3 null brains26. The combination of upregulated BDNF and increased brain size in male ZnT3 null mice suggests the interesting possibility that BDNF upregulation is one of the factors that causes large brains as well as autism phenotypes in these mice.…”

Section: Discussionsupporting

confidence: 91%

“…Because mammalian brains contain a large and dynamic pool of zinc in glutamatergic synaptic vesicles (synaptic zinc), it is plausible that synaptic zinc plays a role in MMP activation and BDNF upregulation around synapses. However, contrary to our expectations, a recent study by Helgager demonstrated that ZnT3 null mice, in which synaptic zinc is absent, show increased levels of BDNF26. Hence, the absence of synaptic zinc, especially during brain development, may cause the upregulation of BDNF by an unidentified mechanism and may possibly induce large brain size and autistic phenotypes.…”

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confidence: 99%

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Autism phenotypes in ZnT3 null mice: Involvement of zinc dyshomeostasis, MMP-9 activation and BDNF upregulation

Yoo

Kim

Yoon

et al. 2016

Sci Rep

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To investigate the role of synaptic zinc in the ASD pathogenesis, we examined zinc transporter 3 (ZnT3) null mice. At 4–5 weeks of age, male but not female ZnT3 null mice exhibited autistic-like behaviors. Cortical volume and neurite density were significantly greater in male ZnT3 null mice than in WT mice. In male ZnT3 null mice, consistent with enhanced neurotrophic stimuli, the level of BDNF as well as activity of MMP-9 was increased. Consistent with known roles for MMPs in BDNF upregulation, 2.5-week treatment with minocycline, an MMP inhibitor, significantly attenuated BDNF levels as well as megalencephaly and autistic-like behaviors. Although the ZnT3 null state removed synaptic zinc, it rather increased free zinc in the cytosol of brain cells, which appeared to increase MMP-9 activity and BDNF levels. The present results suggest that zinc dyshomeostasis during the critical period of brain development may be a possible contributing mechanism for ASD.

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Section: Discussionsupporting

confidence: 91%

contrasting

confidence: 99%

Autism phenotypes in ZnT3 null mice: Involvement of zinc dyshomeostasis, MMP-9 activation and BDNF upregulation

Yoo

Kim

Yoon

et al. 2016

Sci Rep

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“…The BDNF levels measured by ELISA were somewhat low relative to levels described in previous reports (e.g., see Helgager et al, 2014). This could be due to methodological aspects of the sample preparation.…”

Section: Bdnf Protein Levelscontrasting

confidence: 70%

“…For certain experiments, samples were acidified during preparation to increase the detection of BDNF (Okragly & Haak-Frendscho, 1997). The acidification procedure was adapted from Helgager et al (2014) and was performed after the samples spent 1 h on ice, but prior to centrifugation. The pH of the samples was adjusted to <3.0 using 1 M HCl, and the samples were left for 20 min at room temperature.…”

Section: Sample Collection and Protein Extractionmentioning

confidence: 99%

“…Similarly, Nakashima et al (2011) showed that TrkB mRNA levels in barrel cortex are reduced in 2-month-old male ZnT3 KO mice. On the other hand, Helgager et al (2014) showed that ZnT3 KO mice, aged 3-6 months, have normal levels of hippocampal TrkB but elevated BDNF, resulting in increased TrkB phosphorylation. And Yoo et al (2016) found that 5-week-old male ZnT3 KO mice have increased levels of TrkB in the hippocampus and cortex, increased mature BDNF and proBDNF in the cortex, and increased mature BDNF but decreased proBDNF in the hippocampus.…”

Section: Introductionmentioning

confidence: 99%

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Brain-derived neurotrophic factor and TrkB levels in mice that lack vesicular zinc: Effects of age and sex

McAllister

Bihelek

Mychasiuk

et al. 2018

Preprint

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ANOVA: analysis of variance; BDNF: brain-derived neurotrophic factor; CNS: central nervous system; ELISA: enzyme-linked immunosorbent assay; KO: knockout; MMP: matrix metalloproteinase; mRNA: messenger RNA; qRT-PCR: quantitative reverse-transcription polymerase chain reaction; TrkB: tropomyosin receptor kinase B; TrkB.T: truncated TrkB; WT: wild type; ZnT3: zinc transporter 3. ABSTRACTIn certain neurons, zinc ions are stored in synaptic vesicles by zinc transporter 3 (ZnT3).Vesicular zinc can then be released synaptically to modulate myriad targets. In vitro evidence indicates that these targets may include brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB). But the effects of vesicular zinc on BDNF and TrkB in the intact brain are unclear. Studies of mice that lack ZnT3 -and, as a result, vesicular zinc -have shown abnormalities in BDNF and TrkB levels, but results have been mixed and are therefore difficult to interpret. This might be caused by differences in the age or sex of mice tested. In the present study, we measured BDNF and TrkB levels in the hippocampus and neocortex, comparing wild type and ZnT3 knockout mice of both sexes at two ages (5 and 12 weeks). We also examined BDNF mRNA expression and protein levels at an intermediate age (8-10 weeks). We found that, regardless of age or sex, BDNF and TrkB protein levels did not differ between wild type and ZnT3 knockout mice. There were sex-specific differences in BDNF protein and mRNA expression, however. BDNF protein levels increased with age in female mice but not in males. And in females, but not males, ZnT3 KO mice exhibited great hippocampal BDNF mRNA expression than wild type mice. We conclude that, at least in naïve mice housed under standard laboratory conditions, elimination of vesicular zinc does not affect BDNF or TrkB protein levels.

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

et al. 2020

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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.

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Brain‐derived neurotrophic factor but not vesicular zinc promotes TrkB activation within mossy fibers of mouse hippocampus in vivo

Cited by 28 publications

References 50 publications

Autism phenotypes in ZnT3 null mice: Involvement of zinc dyshomeostasis, MMP-9 activation and BDNF upregulation

Autism phenotypes in ZnT3 null mice: Involvement of zinc dyshomeostasis, MMP-9 activation and BDNF upregulation

Brain-derived neurotrophic factor and TrkB levels in mice that lack vesicular zinc: Effects of age and sex

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

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