Microglial ROCK is essential for chronic methylmercury-induced neurodegeneration.

Methylmercury (MeHg), an environmental pollutant, causes serious damage to many organs. Effects on the CNS were initially thought to arise from MeHg acting directly on neurons, but it also has significant effects on non-neuronal cells such as microglia. Microglia, which are very sensitive to changes in the brain environment, show various phenotypes. We previously reported that upon short exposure to MeHg (MeHgshort ) at low concentration, microglia exhibited a neuroprotective phenotype; whereas, long-term exposure (MeHglong ) induced a neurotoxic phenotype of microglia. However, contributions of microglia to MeHg-induced CNS damage remain unknown. Even at very low concentrations, MeHglong but not MeHgshort caused significant neuronal damage associated with an increased number of reactive microglia in cortical slices from wild-type (WT) mice. Two-photon imaging of cortical slices from Iba1-GFP mice revealed that microglia in control conditions exhibited elongated and complex processes with high motility. MeHglong caused a significant reduction in process motility, retraction of processes, and hypertrophic cell bodies, indicating activated microglia. Moreover, MeHglong -treated microglia upregulated pro-inflammatory molecues, suggesting a change into a neurotoxic phenotype of microglia. As a molecular target, Rho-kinase (ROCK) was found to be key for controlling microglial reactivity and neurotoxicity. Expression level of ROCK was increased by MeHglong in WT slices, which was abolished by minocycline or Y-27632. We confirmed that MeHg directly activates microglial ROCK pathways prepared from WT mice. In addition, MeHg-evoked damage of primary neurons was significantly enhanced by the presence of microglia from WT mice, but offset by minocycline or Y-27632. Taken together, our data demonstrate that MeHg causes neurodegeneration by inducing a neurotoxic microglia phenotype via a ROCK-mediated mechanism.