In Vitro Models for Methylmercury Neurotoxicity: Effects on Glutamatergic Cerebellar Granule Neurons

Abstract

Methylmercury (MeHg), a relevant persistent environmental contaminant, is widely recognized as a potent neurotoxicant in humans. The clinical features of MeHg-intoxicated people are characterized by neurological dysfunction that induces cerebellar-based ataxia, generalized extremity weakness, and sensory disturbances including speech, vision, and hearing impairment, which correlate with the loss of neurons from several areas of the brain, among them the cerebellar granule cell (CGC) layer. CGCs are glutamatergic neurons that are successfully grown in vitro. Here, we report the effects of short and long term exposure to MeHg on primary cultures of CGCs. Short exposure to micromolar concentrations of MeHg inhibits neuronal glutamate uptake and induces the release of endogenous glutamate, the increase of intracellular calcium and of oxidative stress. After continuous exposure to low MeHg concentration (in the nanomolar range) oxidative stress results in lipid peroxidation and cell death which are reduced by the glutathione peroxidase (GPx)-enhancing antioxidant probucol or by overexpressing GPx in the cells. Decreased phosphorylation and translocation of cofi lin from the cytosol to the mitochondria are also early hallmarks of MeHg-induced toxicity in cultured cerebellar granule neurons.