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Functional Neuroimaging Using Ultrasonic Blood-brain Barrier Disruption and Manganese-enhanced MRI
Published on: July 12, 2012
Selective vulnerability of pallidal neurons in the early phases of manganese intoxication
Abstract:
Prolonged exposure to manganese in mammals may cause an extrapyramidal disorder characterized by dystonia and rigidity. Gliosis in the pallidal segments underlies the well-established phase of the intoxication. The early phase of the intoxication may be characterized by psychic, nonmotor signs, and its morphological and electrophysiological correlates are less defined. In a rat model of manganese intoxication (20 mg/ml in drinking water for 3 months), neither neuronal loss nor gliosis was detected in globus pallidus (GP). However, a striking vulnerability of manganese-treated GP neurons emerged. The majority of GP neurons isolated from manganese-treated rats died following brief incubation in standard dissociation media. In addition, patch-clamp recordings in the whole-cell configuration were not tolerated by surviving GP neurons. Neither coeval but untreated GP neurons nor striatal ones manifested analogous susceptibility. Using the perforated-patch mode of recording we attempted at identifying the functional hallmarks of GP vulnerability: in particular, voltage-gated calcium currents and glutamate-induced currents were examined. Manganese-treated GP neurons exhibited calcium currents similar to control cells aside from a slight reduction in the dihydropyridine-sensitive current facilitation. Strikingly, manganese-treated GP cells--but not striatal ones--manifested peculiar responses to glutamate, since repeated applications of the excitatory amino acid, at concentrations which commonly promote desensitizing responses, produced instead an irreversible cell damage. Possible mechanisms are discussed.
Insights
Manganese exposure causes early neuronal vulnerability in rat globus pallidus (GP) neurons, leading to cell death and damage. This study reveals a novel mechanism of manganese neurotoxicity, impacting non-motor symptoms.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Prolonged manganese exposure can lead to extrapyramidal disorders with dystonia and rigidity.
- Gliosis in pallidal segments is a known hallmark of manganese intoxication.
- Early-phase manganese toxicity presents with non-motor symptoms, but its cellular mechanisms are poorly understood.
Purpose of the Study:
- To investigate the early cellular effects of manganese exposure on globus pallidus (GP) neurons in a rat model.
- To identify functional changes and vulnerabilities in GP neurons following manganese intoxication.
Main Methods:
- Rats were exposed to manganese in drinking water for 3 months.
- Neuronal viability was assessed after isolation from the globus pallidus.
- Electrophysiological techniques, including patch-clamp recordings (whole-cell and perforated-patch), were used to examine neuronal function.
- Voltage-gated calcium currents and glutamate-induced currents were analyzed.
Main Results:
- Manganese-treated GP neurons exhibited increased vulnerability, with a majority dying upon isolation.
- Surviving GP neurons showed intolerance to whole-cell patch-clamp recordings.
- Manganese-treated GP neurons displayed peculiar, irreversible cell damage upon repeated glutamate application, unlike striatal neurons.
- Calcium currents were largely similar to controls, with minor changes in dihydropyridine-sensitive current facilitation.
Conclusions:
- Manganese intoxication induces a striking vulnerability in globus pallidus neurons, preceding overt neuronal loss or gliosis.
- This vulnerability is characterized by excitotoxicity upon glutamate stimulation, suggesting a novel mechanism for early manganese neurotoxicity.
- These findings may explain the non-motor symptoms associated with the early stages of manganese exposure.
