Resveratrol attenuates methylmercury-induced neurotoxicity by modulating synaptic homeostasis

Methylmercury (MeHg) exposure has received global attention. To date, studies of the developmental toxicity of MeHg have focused on its effects on the nervous system. Resveratrol (RSV) is a neuroprotective molecule that has been shown to be a potential enhancer of hippocampal plasticity. However, there remains a lack of evidence for its protective effects against MeHg neurotoxicity, particularly with respect to synaptic homeostasis. In the current study, in vivo and in vitro results both indicated that MeHg causes a reduction in dendritic length and branching of neurons and decreases the levels of the hippocampal neuronal synaptic protein markers SYN and PSD-95. Consistent with these findings, the Morris Water Maze results demonstrated that MeHg induces cognitive deficits in pups. Dendritic spines are the main postsynaptic components of excitatory synapses and are key structures involved in memory and cognition. The disruption of synaptic homeostasis is controlled by the miR-9-5p/FOXP2 axis. Here, RSV was found to upregulate miR-9-5p expression and downregulate MeHg-induced neurotoxicity, thereby minimizing cytotoxicity in primary hippocampal neurons and effectively attenuating MeHg-induced neurotoxicity. At the same time, RSV ameliorated the perinatal MeHg exposure-induced impairments in synaptic plasticity, spinal-related pathways and learning memory capacity in pups, as well as the pathological changes in the hippocampus. In conclusion, these data suggest that the developmental neurotoxicity of MeHg is associated with damage to synaptogenesis, which is corrected by RSV intervention.