Distortions in bipeak interval timing by chronic methylmercury exposure are attenuated by the L-type Ca++ channel blocker isradipine: Effects of relative and absolute target duration and duration of exposure.
Type of DegreePhD Dissertation
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Nigralstriatal dopamine neurons have a unique, Cav1.3, L-type Ca2+ channel that exhibits rhythmic oscillations in Ca2+, conferring pacemaking activities. This may make them vulnerable to Parkinson’s Disease (PD) or methylmercury (MeHg) exposure, as both are linked to disrupted Ca2+ regulation. Isradipine (ISR), an L-type Ca++ blocker, prevents PD in model systems. Distortions in interval timing, including the migration effect and gross deviations from the scalar property, are behavioral correlates of PD. In the present experiments, timing was assessed in retired breeder, BALB/c mice (~9 months) using the bi-peak interval choice (PIC) procedure. To assess MeHg-induced distortions in timing and investigate the potential role of Ca2+ regulation, mice were chronically exposed to 0 or 5 ppm MeHg and 0 or 2 ppm ISR. During Phase 1, early into exposure and arranging target durations of 8-s and 32-s, MeHg caused the short target duration to be overestimated and the long to be underestimated, conforming to Vierordt’s law. During Phase 2, later in exposure and when target durations were 12-s and 24-s, MeHg caused both target durations to be grossly underestimated. In both phases, MeHg increased the relative variability in timing and caused greater deviations from the scalar property. Importantly, ISR eliminated all MeHg-induced effects on timing variability and any migration effects in timing accuracy. A model-comparison approach, employing theory from the Behavioral Theory of Timing, the Pseudo-Logistic Model, and recent Bayesian models, revealed that these MeHg-induced distortions were due to large reductions in pacemaker/clock speed and increased variability in its regulation. These results add further evidence that one potential way in which MeHg exerts its toxicity is by disrupting Ca2+ functioning in nigrostriatal DAergic-neurons and suggest that PD and MeHg may disrupt similar neurobehavioral systems.