124. Characterizing global behavioral deficits and response to TLR4 stimulation in a murine model of Wilson’s disease

Abstract

Wilson’s disease is a fatal genetic disorder that worldwide affects approximately one in 30,000 people. The autosomal recessive genetic mutation in the ATB7B gene that causes Wilson’s disease leads to a progressive accumulation of copper in the brain. Neurological symptoms tend to present after age 20, and may include lack of balance, slurred speech, masked facial expression, dystonia, as well as cognitive dysfunction. To examine potential cognitive and executive-function deficits, we utilized the toxic milk mouse (TxJ, n = 21) as a murine model of Wilson’s disease. Wild type (WT) control animals (C3He, n = 15) showed a cerebellar copper concentration of 2.18 μg/g, while TxJ animals had 4.18 μg/g at maximum load. Both strains were tested for motor coordination on a rotarod task, which showed consistently worse performance for TXJ mice compared to WT controls. This was evident as significantly lower latencies to fall [representative average (±SE) at 24RPM - C3He: 43.3s (3.4s), TxJ: 28.3s (3.2s)]. Interestingly, the TxJ animals displayed attenuated indices of anxiety-like behavior in an elevated plus maze task when stimulated with the TLR4 ligand lipopolysaccharide [ratio of time spent in open arm/closed arm (±SE): C3He ( n = 10): 0.06 (0.02), TxJ ( n = 14): 0.46 (0.13)]. Preliminary data in an operant learning paradigm suggests a delay in learning for TxJ mice. We are currently testing if this is due to increased microglia cell activation in the hippocampus.