Cholestatic ABCB4-deficient mice reveal depression/anxiety-like behavior
Aims: Depression is commonly associated with chronic liver disease; however, its causality remains largely unknown (Lee et al. Psychosomatics 2013;54:52 – 9). Quantitative phenotypes are linked to psychiatric disorders, thus genetic studies in mice might help to identify modifier genes that influence behavior. Our aim now was to characterize the behavioral phenotype in the ABCB4-deficient (Abcb4–/– ) mouse, a well-established model for chronic cholestatic liver disease.
Methods: We used the Open Field (OF) test, which evaluates spontaneous exploratory drive, reactivity to novelty and emotionality. Specifically, time courses of distance travelled, including speed of movement and time spent in the center, and rearing frequencies were noted in 5-min-intervals. Additionally, we assessed sensorimotor gating by Prepulse Inhibition (PPI) one week after OF at different intensities. The tests were carried out with 18 Abcb4–/– mice and 20 BALB/cJ wild-type controls, aged 10 to 13 weeks.
Results: OF revealed significant genotype effects (p < 0.001) with consistently decreased locomotor activity characterized by reduced speed of movement and increased avoidance of the peripheral and central zones in Abcb4–/– mice. The time course of unconditioned behavior of Abcb4–/– mice in the OF revealed a significant genotype effect on the curve shape of the measured parameters. Furthermore, we detected a significant decrease in rearing activity for Abcb4–/– mice as compared to controls (total frequency 47.8 ± 8.4 vs. 99.0 ± 8.6 [events], p < 0.001). Assessment of PPI revealed a deficit at 69 dB intensity in female Abcb4–/– mice only.
Conclusions: Abcb4–/– mice show greater anxiety behavior and reduced exploratory activity compared to wild-type controls. However, given that ABCB4 is almost exclusively expressed in liver but not in brain, the induced locomotor behavioral alterations are most likely secondary, e.g. caused by neurochemical changes associated with the significantly reduced serum vitamin D levels recently described by us in Abcb4–/– mice. Of note, this model resembles the link between chronic liver diseases and increased stress susceptibility observed in humans.