Affective and cognitive behavior in the alpha-galactosidase A deficient mouse model of Fabry disease

Abstract

Fabry disease is an X-linked inherited lysosomal storage disorder with intracellular accumulation of globotriaosylceramide (Gb3) due to α-galactosidase A (α-Gal A) deficiency. Fabry patients frequently report of anxiety, depression, and impaired cognitive function. We characterized affective and cognitive phenotype of male mice with α-Gal A deficiency (Fabry KO) and compared results with those of age-matched male wildtype (WT) littermates. Young (3 months) and old (≥ 18 months) mice were tested in the naïve state and after i.pl. injection of complete Freund`s adjuvant (CFA) as an inflammatory pain model. We used the elevated plus maze (EPM), the light-dark box (LDB) and the open field test (OF) to investigate anxiety-like behavior. The forced swim test (FST) and Morris water maze (MWM) were applied to assess depressive-like and learning behavior. The EPM test revealed no intergroup difference for anxiety-like behavior in naïve young and old Fabry KO mice compared to WT littermates, except for longer time spent in open arms of the EPM for young WT mice compared to young Fabry KO mice (p<0.05). After CFA injection, young Fabry KO mice showed increased anxiety-like behavior compared to young WT littermates (p<0.05) and naïve young Fabry KO mice (p<0.05) in the EPM as reflected by shorter time spent in EPM open arms. There were no relevant differences in the LDB and the OF test, except for longer time spent in the center zone of the OF by young WT mice compared to young Fabry KO mice (p<0.05). Complementary to this, depression-like and learning behavior were not different between genotypes and age-groups, except for the expectedly lower memory performance in older age-groups compared to young mice. Our results indicate that genetic influences on affective and cognitive symptoms in FD may be of subordinate relevance, drawing attention to potential influences of environmental and epigenetic factors.

Toll-like receptor 4 deficiency ameliorates β2-microglobulin induced age-related cognition decline due to neuroinflammation in mice

“…Morris water maze (MWM) was conducted 24 day after the B2M treatment as previously described [52]. The circular water maze pool (120 cm in diameter, 50 cm deep) was located in a dimly lit room.…”

GM2 ganglioside accumulation causes neuroinflammation and behavioral alterations in a mouse model of early-onset Tay-Sachs disease.

“…The passive avoidance test was used to detect cognitive learning and memory deficits [44]. We found (Fig.…”

“…Up-regulation of cytokines and their receptors within the CNS during inflammation, and concomitant effects on brain function, have been reported [6]. The Morris water maze task was used to detect spatial learning and memory deficits [43][44][45][46]. We used a two-way ANOVA to analyze the data.…”

“…7E, F). For a more specific measure of muscle strength, grip strength tests were also performed [44,47]. The forelimb assessments demonstrated no significant change in strength of the 2.5-month-old mice (Fig.…”

Altered Gene Expression in Prefrontal Cortex of a Fabry Disease Mouse Model

“…In line with these pathologies, different forms of cognitive deficits have been reported in FD patients, spanning from higher prevalence of depression and anxiety to impairment of information processing and attention (Schermuly et al, 2011 ; Bolsover et al, 2014 ; Sigmundsdottir et al, 2014 ), as well as impaired long-term verbal memory (Cocozza et al, 2018 ). These are reflected to some extent in a transgenic FD mouse model which shows increased anxiety-like behavior (Hofmann et al, 2017 ).…”