A bout analysis reveals age-dependent methylmercury neurotoxicity and nimodipine neuroprotection: Implications for the role of calcium homeostasis in aging

Abstract

Learning and sensorimotor function decline in normal aging and these deficits may be related to elevations in intracellular calcium (Ca2+) levels [Ca2+]i. The neurotoxicity of methylmercury (MeHg), a ubiquitous environmental contaminant, also appears to be mediated, in part, by elevated [Ca2+]i. Calcium channel blockers (CCBs), which can lower [Ca2+]I, may confer neuroprotection against aging and/or MeHg-induced dysfunction. Studying the effects of chronic MeHg and/or CCB exposure presents a unique way by which to study potential mechanisms of aging. Experiments 1 and 2, conducted simultaneously, chronically exposed two age cohorts (adults and retired breeders) of BALB/c mice to 0 or 10 ppm MeHg and 0 or 200 ppm nimodipine, a CCB, for approximately 8.5 months. Experiment 1 investigated high-rate nose-poking meanwhile Experiment 2 investigated wheel-running and rotarod performance. A bout analysis approach was used to estimate motor and motivational contributions to both nose-poking and wheel-running. Methylmercury produced age-independent mortality and nimodipine afforded protection in an age-dependent manner; there was greater protection in younger animals. Reliably, MeHg-induced motor impairment of nose-poking, wheel-running, and rotarod performance appeared early into exposure while motivational deficits appeared only near mortality. Nimodipine delayed the onset of MeHg-induced behavior deficits and this protection was more pronounced in younger animals. For nose-poking, latency to motor impairment was shorter in older animals than in younger animals. These results provide a comprehensive profile of adult-onset MeHg exposure and also provide support for the use of a bout analysis approach as an analytical tool to delineate between motor and motivational components of behavior.