Subchronic methylmercury exposure disrupts forebrain inhibitory circuits and induces psychomotor abnormalities in...

Mercury is a persistent global pollutant, and methylmercury (MeHg) remains a major environmental health concern because human exposure continues through seafood consumption and severe contamination events. Although MeHg neurotoxicity has classically been linked to cerebellar and sensorimotor dysfunction, clinical and epidemiological studies have also reported psychiatric and behavioral disturbances, for which the underlying circuit pathology remains unclear. Here, we investigated whether subchronic MeHg exposure disrupts inhibitory control in forebrain circuits involved in emotional and behavioral regulation. Male mice were given 30 ppm MeHg in drinking water for up to 8 weeks, a high-dose paradigm designed to model severe subchronic MeHg intoxication and examine circuit-level neuropathology and behavior. MeHg exposure produced region-selective neuronal injury, characterized by increased TUNEL labeling and reduced NeuN-positive cells, in the anterior cingulate cortex, nucleus accumbens, mediodorsal thalamus, central amygdala, and basolateral amygdala. Across these regions, the inhibitory neuronal marker glutamate decarboxylase 65/67 (GAD65/67) was consistently reduced, whereas the excitatory presynaptic terminal markers vesicular glutamate transporter 1 and 2 (VGLUT1/2) were relatively preserved. c-Fos-positive cells showed an overall increasing trend across these regions, reaching statistical significance in the anterior cingulate cortex (ACC); together, this pattern was consistent with a shift toward forebrain circuit disinhibition. Behaviorally, MeHg-exposed mice developed hyperactivity and stereotypic jumping behavior. Importantly, the GABAergic modulator chlormezanone reduced hyperactivity and abolished stereotypic jumping. Together, these findings support forebrain inhibitory dysfunction as a mechanistically relevant feature of MeHg neurotoxicity and suggest that impaired inhibitory control contributes to MeHg-induced psychomotor abnormalities. This study expands the neuropathological framework of MeHg toxicity beyond classical sensorimotor lesions and supports the inclusion of circuit-level neurobehavioral endpoints in hazard characterization of environmental neurotoxicants.