title: A zebrafish model of manganism reveals reversible and treatable symptoms that are independent of neurotoxicity.
abstract: Manganese (manganese ion; referred to as Mn) is essential for neuronal function, yet it is toxic at high concentrations. Environmental and occupational exposure to high concentrations of Mn causes manganism, a well-defined movement disorder in humans, with symptoms resembling Parkinson's disease (PD). However, manganism is distinct from PD and the neural basis of its pathology is poorly understood. To address this issue, we generated a zebrafish model of manganism by incubating larvae in rearing medium containing Mn. We find that Mn-treated zebrafish larvae exhibit specific postural and locomotor defects. Larvae begin to float on their sides, show a curved spine and swim in circles. We discovered that treatment with Mn causes postural defects by interfering with mechanotransduction at the neuromasts. Furthermore, we find that the circling locomotion could be caused by long-duration bursting in the motor neurons, which can lead to long-duration tail bends in the Mn-treated larvae. Mn-treated larvae also exhibited fewer startle movements. Additionally, we show that the intensity of tyrosine hydroxylase immunoreactivity is reversibly reduced after Mn-treatment. This led us to propose that reduced dopamine neuromodulation drives the changes in startle movements. To test this, when we supplied an external source of dopamine to Mn-treated larvae, the larvae exhibited a normal number of startle swims. Taken together, these results indicate that Mn interferes with neuronal function at the sensory, motor and modulatory levels, and open avenues for therapeutically targeted studies on the zebrafish model of manganism.
authors.affiliation: Department of Chemical Sciences, Tata Institute of Fundamental Research, 1 Homi Bhabha Road, Colaba, Mumbai-400005, India.
authors.forename: Subha
authors.initials: S
authors.lastname: Bakthavatsalam
authors.affiliation: National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bellary Road, Bangalore-560065, India.
authors.forename: Shreya
authors.initials: S
authors.lastname: Das Sharma
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, 1 Homi Bhabha Road, Colaba, Mumbai-400005, India.
authors.forename: Mahendra
authors.initials: M
authors.lastname: Sonawane
authors.affiliation: National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bellary Road, Bangalore-560065, India. vatsala@ncbs.res.in ankona@tifr.res.in.
authors.forename: Vatsala
authors.initials: V
authors.lastname: Thirumalai
authors.affiliation: Department of Chemical Sciences, Tata Institute of Fundamental Research, 1 Homi Bhabha Road, Colaba, Mumbai-400005, India. vatsala@ncbs.res.in ankona@tifr.res.in.
authors.forename: Ankona
authors.initials: A
authors.lastname: Datta
mesh_terms: D000818:Animals; D008345:Manganese / Q000633:toxicity*; D009420:Nervous System / Q000187:drug effects* / Q000201:enzymology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015027:Zebrafish
chemical_list: D008345:Manganese; D014446:Tyrosine 3-Monooxygenase
keywords: Dopaminergic neurons; Fictive motor patterns; Manganism; Mechanotransduction; Zebrafish