Ecotoxicology and Environmental Safety (Nov 2021)
miR-29a and the PTEN–GSK3β axis are involved in aluminum-induced damage to primary hippocampal neuronal networks
Abstract
We previously reported that aluminum (Al) can cause a range of neurotoxic injuries including progressive irreversible synaptic structural damage and synaptic dysfunction, and eventually neuronal deaths. Mechanism of Al-induced electrophysiological and neuronal connectivity changes in neurons may indicate damage to the neuronal network. Here, mouse primary hippocampal neurons were cultured on micro-electrode array (MEA)- and high-content analysis (HCA)-related plates, showing that Al exposure significantly inhibited hippocampal neuronal electrical spike activity and neurite outgrowth characterized by a reduction in neurite branching and a decrease in the average total neurite length in relation to both Al dose and time of incubation. In recent years, miR-29a/ phosphatase and tensin homolog (PTEN) have been found to play pivotal roles in the morphogenesis of neurons, it has been confirmed in vitro and in vivo that the PTEN–Glycogen synthase kinase-3β (GSK-3β) axis regulates neurite outgrowth. The present study demonstrated that increases in Al exposure and dose gradually reduce miR-29a expression. Up-regulation of miR-29a in the hippocampal neurons by lentivirus transfection reversed the decrease in electrical spike activity and the reduction in both neurite branching and length induced by Al. Moreover, miR-29a suppressed the expression of PTEN and increased the level of phosphorylated Protein Kinase B (p-AKT) and p-GSK-3β which were inhibited by the Al treatment. This suggests that miR-29a is critically involved in the functional and structural neuronal damage induced by Al and is a potential target for Al neurotoxicity. Moreover, the reduction of neurite length and branching induced by Al exposure was regulated by miR-29a and its target neuronal PTEN–GSK3β signaling pathway, which also represents a possible mechanism of Al-induced the inhibition of the electrical activity. Collectively, Al-induced damage to the neuronal network occurred through miR-29a-mediated alterations of the PTEN–GSK3β signaling pathway.
