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Effects of trace metal profiles characteristic for autism on synapses in cultured neurons.

Hagmeyer S, Mangus K, Boeckers TM, Grabrucker AM - Neural Plast. (2015)

Bottom Line: Additionally, synaptic protein levels of GluN2a and Shanks are reduced.Although Zn supplementation is able to rescue the aforementioned alterations, Zn deficiency is not solely responsible as causative factor.Thus, we conclude that balancing Zn levels in ASD might be a prime target to normalize synaptic alterations caused by biometal dyshomeostasis.

View Article: PubMed Central - PubMed

Affiliation: WG Molecular Analysis of Synaptopathies, Neurology Department, Neurocenter of Ulm University, 89081 Ulm, Germany.

ABSTRACT
Various recent studies revealed that biometal dyshomeostasis plays a crucial role in the pathogenesis of neurological disorders such as autism spectrum disorders (ASD). Substantial evidence indicates that disrupted neuronal homeostasis of different metal ions such as Fe, Cu, Pb, Hg, Se, and Zn may mediate synaptic dysfunction and impair synapse formation and maturation. Here, we performed in vitro studies investigating the consequences of an imbalance of transition metals on glutamatergic synapses of hippocampal neurons. We analyzed whether an imbalance of any one metal ion alters cell health and synapse numbers. Moreover, we evaluated whether a biometal profile characteristic for ASD patients influences synapse formation, maturation, and composition regarding NMDA receptor subunits and Shank proteins. Our results show that an ASD like biometal profile leads to a reduction of NMDAR (NR/Grin/GluN) subunit 1 and 2a, as well as Shank gene expression along with a reduction of synapse density. Additionally, synaptic protein levels of GluN2a and Shanks are reduced. Although Zn supplementation is able to rescue the aforementioned alterations, Zn deficiency is not solely responsible as causative factor. Thus, we conclude that balancing Zn levels in ASD might be a prime target to normalize synaptic alterations caused by biometal dyshomeostasis.

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Related in: MedlinePlus

Effect of trace metals on synapse formation or stability. While the observed decrease in synapse number can be correlated with the overall cell death of neurons in culture for Cd, Cu, and Hg (left panel), no correlation was found for Al, Fe, and Pb that did not significantly alter cell health. Mg shows only a weak correlation due to its nontoxic effects on neurons over a wide concentration range. Both Zn and Se may display even increased synapse numbers despite ongoing cell death.
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fig2: Effect of trace metals on synapse formation or stability. While the observed decrease in synapse number can be correlated with the overall cell death of neurons in culture for Cd, Cu, and Hg (left panel), no correlation was found for Al, Fe, and Pb that did not significantly alter cell health. Mg shows only a weak correlation due to its nontoxic effects on neurons over a wide concentration range. Both Zn and Se may display even increased synapse numbers despite ongoing cell death.

Mentions: Since, for some metal ions, we could determine an effect on synapses independent of a possible cellular toxicity (Figure 2), a role of these metals in synapse formation and/or stabilization is likely. For example, Mg shows only a weak correlation due to its nontoxic effects on neurons over a wide concentration range. Additionally, supplementation of both Zn and Se, in low concentrations increased synapse density, which then can be found increased compared to untreated control despite ongoing cell death.


Effects of trace metal profiles characteristic for autism on synapses in cultured neurons.

Hagmeyer S, Mangus K, Boeckers TM, Grabrucker AM - Neural Plast. (2015)

Effect of trace metals on synapse formation or stability. While the observed decrease in synapse number can be correlated with the overall cell death of neurons in culture for Cd, Cu, and Hg (left panel), no correlation was found for Al, Fe, and Pb that did not significantly alter cell health. Mg shows only a weak correlation due to its nontoxic effects on neurons over a wide concentration range. Both Zn and Se may display even increased synapse numbers despite ongoing cell death.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4352758&req=5

fig2: Effect of trace metals on synapse formation or stability. While the observed decrease in synapse number can be correlated with the overall cell death of neurons in culture for Cd, Cu, and Hg (left panel), no correlation was found for Al, Fe, and Pb that did not significantly alter cell health. Mg shows only a weak correlation due to its nontoxic effects on neurons over a wide concentration range. Both Zn and Se may display even increased synapse numbers despite ongoing cell death.
Mentions: Since, for some metal ions, we could determine an effect on synapses independent of a possible cellular toxicity (Figure 2), a role of these metals in synapse formation and/or stabilization is likely. For example, Mg shows only a weak correlation due to its nontoxic effects on neurons over a wide concentration range. Additionally, supplementation of both Zn and Se, in low concentrations increased synapse density, which then can be found increased compared to untreated control despite ongoing cell death.

Bottom Line: Additionally, synaptic protein levels of GluN2a and Shanks are reduced.Although Zn supplementation is able to rescue the aforementioned alterations, Zn deficiency is not solely responsible as causative factor.Thus, we conclude that balancing Zn levels in ASD might be a prime target to normalize synaptic alterations caused by biometal dyshomeostasis.

View Article: PubMed Central - PubMed

Affiliation: WG Molecular Analysis of Synaptopathies, Neurology Department, Neurocenter of Ulm University, 89081 Ulm, Germany.

ABSTRACT
Various recent studies revealed that biometal dyshomeostasis plays a crucial role in the pathogenesis of neurological disorders such as autism spectrum disorders (ASD). Substantial evidence indicates that disrupted neuronal homeostasis of different metal ions such as Fe, Cu, Pb, Hg, Se, and Zn may mediate synaptic dysfunction and impair synapse formation and maturation. Here, we performed in vitro studies investigating the consequences of an imbalance of transition metals on glutamatergic synapses of hippocampal neurons. We analyzed whether an imbalance of any one metal ion alters cell health and synapse numbers. Moreover, we evaluated whether a biometal profile characteristic for ASD patients influences synapse formation, maturation, and composition regarding NMDA receptor subunits and Shank proteins. Our results show that an ASD like biometal profile leads to a reduction of NMDAR (NR/Grin/GluN) subunit 1 and 2a, as well as Shank gene expression along with a reduction of synapse density. Additionally, synaptic protein levels of GluN2a and Shanks are reduced. Although Zn supplementation is able to rescue the aforementioned alterations, Zn deficiency is not solely responsible as causative factor. Thus, we conclude that balancing Zn levels in ASD might be a prime target to normalize synaptic alterations caused by biometal dyshomeostasis.

Show MeSH
Related in: MedlinePlus