Cognitive behavioral dysregulation induced by low-level lead, cadmium, and mercury co-exposure is linked to AMPA receptor-associated with E/I imbalance.

We previously found low-level heavy metals lead (Pb), cadmium (Cd), and mercury (Hg) co-exposure impairs cognition even at their respective no observed adverse effect levels. However, the underlying mechanisms and complex interactions within mixture remain poorly understood from neurobiological basis perspective. Therefore, following low-level Pb, Cd, and Hg co-exposure, we systematically investigated the effects of that on synaptic efficiency, excitation/inhibition (E/I) balance, active neurons, and cognitive behavior impairment using electrophysiology, c-Fos active neuron labeling, and cognitive behavioral tests. In vitro factorial design experiments indicated that very low-level Pb, Cd, and Hg co-exposure specifically disrupted hippocampal synaptic transmission mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, potentially serving as a neurobiological basis for cognitive impairment following that exposure. This synaptic dysfunction may further shift E/I balance toward hyperexcitability, with increasing baseline hippocampal neuronal activity and inducing mice risk-taking behavior in resting state. Paradoxically, with mild stimulation by foot-shock, co-exposure attenuated both neuronal and behavioral responsiveness. Further analysis showed that while baseline active excitatory neurons and vGluT1 expression (particularly in dentate gyrus) were elevated, their stimulus-evoked plasticity was impaired, following low-level Pb, Cd, and Hg co-exposure. Overall, our findings suggest that AMPA receptor-associated E/I imbalance from low-level Pb, Cd, and Hg co-exposure was linked to altered neuronal activity patterns and impaired cognitive behavioral regulation. This study provides valuable insights for researchers and managers in revising safety thresholds, exploring mechanisms, and searching interventions for low-level heavy metal exposure.