Neurochemical and Behavioral Characteristics of Toxic Milk Mice: An Animal Model of Wilson’s Disease

Adam Przybyłkowski,Tomasz Grygorowicz,Grażyna Gromadzka,Andrzej Członkowski,Katarzyna Jabłonka-Salach,Anna Schnejder-Pachołek,Adriana Wawer,Ewa Bulska

doi:10.1007/s11064-013-1111-3

Adam Przybyłkowski, Tomasz Grygorowicz + Show 6 more

Open Access

https://doi.org/10.1007/s11064-013-1111-3

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Abstract

Toxic milk mice have an inherited defect of copper metabolism. Hepatic phenotype of the toxic milk mice is similar to clinical findings in humans suffering from Wilson’s disease (WND). In the present study, neurotransmitter system and locomotor performance in toxic milk mice was examined to verify the feasibility of this animal model for studying neuropathology of WND. Mice aged 2 and 12 months were used in the experiment. The mice were tested according to rotarod and footprint protocols. Monoamine content in brain structures was measured by high performance liquid chromatography. In order to detect neuronal loss, expression of enzymes specific for dopaminergic [tyrosine hydroxylase (TH)], noradrenergic (dopamine beta-hydroxylase) and serotoninergic [tryptophan hydroxylase (TPH)] neurons was analyzed by Western blot. The 12-month-old toxic milk mice demonstrated impaired locomotor performance in behavioral tests. Motor deficits were accompanied by increased copper and serotonin content in different brain regions and slight decrease in dopamine concentration in the striatum. The expression of TH, dopamine beta-hydroxylase and TPH in the various brain structures did not differ between toxic milk mice and control animals. Despite differences in brain pathology between humans and rodents, further exploration of neuronal injury in toxic milk mice is warranted to broaden the understanding of neuropathology in WND.

Highlights

Neurotransmitter system and locomotor performance in toxic milk mice was examined to verify the feasibility of this animal model for studying neuropathology of Wilson’s disease (WND)
Involvement of liver in toxic milk mice characterized by steatosis, mild inflammation and gross nodularity resembles pathology observed in humans affected by WND [1, 5, 6]
No significant strain or age differences were detected in terms of iron content with the exception of hippocampus of old toxic milk mice, where iron concentration was markedly reduced in comparison to the control group (Fig. 2b)

Summary

Introduction

Toxic milk (tx) is an autosomal recessive mutation in Atp7b gene in C57BL/6J mice strain This mutation arose spontaneously in Neurochem Res (2013) 38:2037–2045 laboratory of University of Massachusetts (MA, USA) and was characterized by Rauch ( this strain will be referred in the text as txR) [3]. The toxic milk mutation detected in The Jackson Laboratory (txJ) is a point mutation at position 2135 (in exon 8) which leads to glycine to aspartic acid (G712D) missense mutation in ATPase [4] This specific mutation has not been reported in any human WND patient; the txJ mice share phenotypic similarities with WND. Involvement of liver in toxic milk mice characterized by steatosis, mild inflammation and gross nodularity resembles pathology observed in humans affected by WND [1, 5, 6]

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