The wide application of lithium in green energy and clinical psychiatry results in ubiquitous occurrence of lithium in aquatic environments. However, researches on the toxicity of lithium are largely confined to acute and/or high-dose scenarios, with insufficient data on its impacts on non-target organisms at environmental levels. The present study investigated the neurotoxicological effects of environmentally relevant concentrations of lithium exposure on yellowstripe goby (Mugilogobius chulae) and the related molecular response mechanisms. The results showed that lithium exposure significantly inhibited the expression of the target protein GSK-3�� in the brain of M. chulae, and induced a series of harmful events including oxidative stress, glutamate accumulation, and even behavioral alteration. The organism mitigated the excitotoxic effects of glutamate accumulation by down-regulating ionotropic glutamate receptors. At the same time, the organism met the energy supply and alleviated oxidative stress by altering mitochondrial function. Notably, the stress regulators FoxOs and sestrins both modulated synaptic sensitivities to enhance the neural signaling and altered the energy metabolism pattern to alleviate energy crisis, all of which were important for maintaining neuronal survival and organismal homeostasis. In conclusion, lithium exposure induced glutamate excitability and led to a series of toxic events. Meanwhile, FoxOs played an important role in neural signaling and homeostatic regulation of energy metabolism in brain. This study furthered the comprehension of the neurotoxic impacts of lithium on aquatic organisms, elucidated the associated molecular mechanisms, and underscored the environmental risks posed by increasing lithium contamination.
