Cadmium (Cd) is a widespread environmental contaminant and a significant risk factor for neurodevelopmental disorders. However, the molecular mechanisms underlying its long-term neurotoxic effects remain incompletely understood. In this study, we investigated the impact of early-life Cd exposure on synaptic signaling pathways critical for brain development and function, with a particular focus on zinc-dependent mechanisms.

Using a rat model of maternal Cd exposure during gestation and lactation, we demonstrate that Cd markedly disrupts zinc homeostasis in the brain by downregulating the synaptic zinc transporter ZnT3, leading to reduced zinc availability at glutamatergic synapses. This deficiency impairs activation of the neurotrophic receptor TrkB and alters brain-derived neurotrophic factor (BDNF) signaling. Consequently, key components of synaptic plasticity are affected, including a significant reduction in the NMDA receptor subunit NR2A, decreased expression of the postsynaptic density protein PSD95, and inhibition of the ERK1/2 signaling pathway.

These molecular alterations are associated with long-lasting deficits in learning abilities and motor function in adult offspring, highlighting the enduring impact of developmental Cd exposure. Importantly, zinc supplementation effectively restores ZnT3 expression, reactivates TrkB–BDNF and NMDAR signaling pathways, and significantly improves neurobehavioral outcomes.

Overall, our findings identify the Zn–BDNF–NMDAR signaling axis as a critical target of Cd-induced neurodevelopmental toxicity and suggest that zinc supplementation may represent a promising therapeutic strategy to mitigate the adverse effects of environmental Cd exposure.