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The GSK-3β/β-Catenin Signaling–Mediated Brain–Derived Neurotrophic Factor Pathway Is Involved in Aluminum-Induced Impairment of Hippocampal LTP In Vivo

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Abstract

The neurotoxic effects of aluminum (Al) are associated with the impairment of synaptic plasticity, the biological basis of learning and memory, the major form of which is long-term potentiation (LTP). The canonical glycogen synthase kinase-3β (GSK-3β)/β-catenin signaling–mediated brain–derived neurotrophic factor (BDNF) pathway has been suggested to play important roles in memory. Thus, Al may affect LTP through this pathway. In this study, a Sprague-Dawley rat model of neurotoxicity was established through intracerebroventricular (i.c.v.) injection of aluminum maltol (Al(mal)3), which was achieved by preimplantation of a cannula into the lateral ventricle. The rats in the control and Al-treated groups received a daily injection of SB216763, an inhibitor of GSK-3β. Electrophysiology and western blot analysis were used to investigate the regulatory effect of the GSK-3β/β-catenin signaling-mediated BDNF pathway on LTP impairment induced by Al(mal)3. The results confirmed that i.c.v. injection of Al(mal)3 significantly suppressed the field excitatory postsynaptic potential (fEPSP) amplitude, as indicated by a decrease in BDNF protein expression, which was accompanied by dose-dependent decreases in β-catenin protein expression and the phosphorylation of GSK-3β at Ser9. Rats that received SB216763, a GSK-3β inhibitor, exhibited higher fEPSP amplitudes than control rats. Furthermore, SB216763 treatment upregulated the hippocampal protein expression of BDNF and β-catenin while increasing the ratio of p-GSK-3β/GSK-3β. From the perspective of the identified β-catenin–BDNF axis, Al impairs hippocampal LTP, possibly through the GSK-3β/β-catenin signaling–mediated BDNF pathway.

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Acknowledgments

We sincerely thank our colleagues for their help and work on the study.

Funding

This work was financially supported by the National Natural Science Foundation of China (nos. 81703202 and 81872599).

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Authors and Affiliations

  1. Department of Occupational Health, School of Public Health, Shanxi Medical University, Taiyuan, China

    Huifang Zhang, Yingchao Han, Ling Zhang, Xiaofang Jia & Qiao Niu

  2. Key Lab of Environmental Hazard and Health of Shanxi Province, Shanxi Medical University, Taiyuan, China

    Huifang Zhang, Yingchao Han, Ling Zhang, Xiaofang Jia & Qiao Niu

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All experiments complied with the rulings of the Institute of Laboratory Animal Research, Division on Earth and Life Sciences, National Institute of Health, USA (Guide for the Care and Use of Laboratory Animals). The research protocol was performed in accordance with the regulations of the Institutional Animal Care and Use Committee of Shanxi Medical University.

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Zhang, H., Han, Y., Zhang, L. et al. The GSK-3β/β-Catenin Signaling–Mediated Brain–Derived Neurotrophic Factor Pathway Is Involved in Aluminum-Induced Impairment of Hippocampal LTP In Vivo. Biol Trace Elem Res 199, 4635–4645 (2021). https://doi.org/10.1007/s12011-021-02582-9

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