Acidified drinking water attenuates motor deficits and brain pathology in a mouse model of a childhood neurodegenerative disorder

Abstract

We recently demonstrated that HCl-acidified drinking water, which is widely used in laboratory animal facilities, had some beneficial effects in the Cln3−/− mouse model of juvenile Batten disease, a neurodegenerative lysosomal storage disorder1. Here we tested if acidified drinking water has therapeutic effects in Cln1R151X nonsense mutant mice, a model of the infantile form of Batten disease. In Cln1R151X mice, acidified drinking water received from weaning prevented the impairment in pole climbing ability measured at 3 and 6 months of age. Histopathological analysis of the brain at 6 months showed that acidified drinking water decreased the amount of lysosomal storage material, reduced astrocytosis in the striatum and somatosensory barrelfield cortex, and attenuated microglial activation in the thalamus. Compared to wild-type mice, the gut microbiota of Cln1R151X mice was markedly different. Acidified drinking water significantly altered the gut microbiota composition of Cln1R151X mice, indicating a contribution of gut bacteria to the therapeutic effects of acidified water. Our results in Cln1R151X mice suggest that acidified drinking water may have beneficial effects for patients with infantile Batten disease. This study also verifies that acidified drinking water can modify disease phenotypes in mouse models, contributing to the inter-laboratory variations in neurological and pathological findings.

Acidified drinking water improves motor function, prevents tremors and changes disease trajectory in Cln2R207X mice, a model of late infantile Batten disease

“…Acidified drinking water restored the muscle strength of Cln2 R207X mice to the WT level, as measured in a wire hanging test ( c ). In agreement with our previous results 7 , 15 , acidified drinking water compromised the performance of WT mice in the vertical pole test: they climbed down and turned downward significantly slower than WT mice receiving non-acidified water ( a,b ). Columns and bars represent mean + SEM and the symbols show the individual data (WT and Cln2 R207X on non-acidified water: 28 and 20 mice in the modified vertical pole test, and 14 and 19 mice in the wire hanging test; WT and Cln2 R207X on acidified water: 16 and 19 mice in both tests).…”

“…In line with our previous findings 7 , 15 , acidified drinking water impaired the performance of WT mice in the vertical pole test: they climbed down and turned downward significantly slower than WT mice receiving non-acidified water (Fig. 1 a,b), indicating an impairment in agility, motor coordination and spatial orientation.…”

“…Acidified drinking water in Cln3 −/− mice had a temporary effect, improving the pole climbing ability at 3 months but not at 6 months of age 6 . In Cln1 R151X mice, however, acidified water prevented the motor impairment at both 3 and 6 months as measured in the pole climbing test 7 . Acidified drinking water had a similar effect on the pole climbing ability of Cln2 R207X mice; they could climb down the vertical pole as quickly as WT mice at 3 months of age (see Fig.…”

“…We have previously tested the effects of acidified drinking water on neurological functions in Cln3 −/− and Cln1 R151X mice, models of juvenile CLN3 and infantile CLN1 diseases 6 , 7 . While Cln3 −/− mice were on the 129S6/SvEv genetic background, Cln1 R151X mice were on the same mixed 129S6/SvEv;C57BL/6J background as Cln2 R207X mice.…”

“…At numerous animal facilities, acidification of drinking water with HCl is used to eliminate pathogenic bacteria. We have recently shown in the Cln3 −/− and Cln1 R151X mouse models of juvenile CLN3 and infantile CLN1 diseases that acidified drinking water attenuated neuropathological changes in a disease-specific manner and provided disease-dependent beneficial effects on neurological function 6 , 7 . In both Cln3 −/− and Cln1 R151X mice, the effects of acidified drinking water were accompanied by significant changes in the gut microbiota composition 6 , 7 .…”