Memory, well-being tests can track Sanfilippo mice disease progression
Mice were given tests at three different ages, representing stages of the disease
Standardized tests that measure memory, motor function, and well-being can be used to track the progression of neurological dysfunction in a mouse model of Sanfilippo syndrome type A, a study shows.
“Our data show that the water cross maze, hind-limb gait, nest building, and burrowing are useful assessments to evaluate neurocognitive function in the [Sanfilippo A] mouse model. They perform consistently and faithfully capture patient disease progression as reported in natural history studies,” the researchers wrote in “Neurocognitive testing in a murine model of mucopolysaccharidosis type IIIA,” which was published in Molecular Genetics and Metabolism Reports.
Sanfilippo type A, or mucopolysaccharidosis type IIIA (MPS IIIA), is marked by neurological problems and behavioral differences that appear in childhood and worsen as the disease progresses. As in all types of Sanfilippo, the disease is driven by the toxic accumulation of heparan sulfate (HS) in brain cells.
Mouse models are a key tool for preclinical research to understand a disease’s biological mechanisms and evaluate potential therapies. Mouse models of Sanfilippo type A have been developed, but what evaluations best measure the disease’s progression isn’t known, leading scientists in Australia to submit mice to behavioral tests at three ages, representing early, middle, and late disease stages. The results were compared with wild-type mice of the same age to see if the Sanfilippo mice showed consistent differences.
Tracking early, middle, late stage Sanfilippo syndrome in mice
“In this study, the aim was to explore which behavior tests produce clear and consistent results, reflect HS storage in the brain and, importantly, may be considered surrogate measures of neurocognitive performance in the MPS IIIA mouse model,” they wrote.
By the disease’s middle stage, Sanfilippo A mice performed markedly worse on the water cross-maze test, a standard measure of memory. The difference was more pronounced in the late stage.
“The water cross-maze revealed memory and learning impairment in MPS IIIA mice from mid-stage disease … reflecting human mid-stage disease cognitive skill regression and dementia,” the researchers wrote.
Measures on the hind-limb gait, which assesses motor function, also showed minor detectable differences at mid-stage. This grew more pronounced by the later stages. There were no clear differences between the groups in the open field test, another type of motor assessment, however.
The disease mice also didn’t show any differences in social behavior. By the late stages, they showed significantly fewer burrowing behaviors and poorer nest construction, however, reflecting a general state of poor well-being.
“Nest building and burrowing assessment results here show well-being is unaffected early in disease, but deteriorates later as the disease progresses,” the researchers wrote. “Further research is needed to determine the utility of well-being assessments in the mice as they may be a useful surrogate measure of life quality in MPS IIIA.”
Across all these assessments, Sanfilippo A mice didn’t display any clear abnormalities at the early stages of disease, even though it’s well-established that, in this model and by this stage, toxic HS buildup is detectable. This discrepancy suggests HS buildup might have to surpass some threshold before it causes symptoms. This warrants further study to see if giving treatment before that threshold is reached offers added “neurocognitive benefit,” the researchers said.