Telencephalic histopathology and changes in behavioural and neural plasticity in a murine model for metachromatic leukodystrophy.

Arylsulfatase A-deficient (ASA(-/-)) mice constitute an animal model for metachromatic leukodystrophy, a lysosomal storage disorder. We had previously examined the behavioural phenotype of these mice, but were unable to distinguish between proper cognitive symptoms and potentially interfering, solely neuromotor impairments. In the present study, T-maze delayed alternation (TMDA) showed that ASA(-/-) mice perform worse than controls already at the age of 6 months in a hippocampus-dependent task that does not require motor proficiency. In addition, long term potentiation (LTP) in the CA1 region of the hippocampus, a cellular correlate of learning and memory, was also impaired in ASA(-/-) mice. Finally, histological analysis of previously unexamined telencephalic and diencephalic structures illustrated sulfatide accumulation in brain areas that are important for cognitive functioning. These include the hippocampus, striatum, internal capsule and diencephalon as well as prefrontal, insular, and motor and somatosensory cortices. Together these data corroborate the usefulness of the model in preclinical evaluations of therapeutic strategies that aim to reverse cognitive defects in the human disease.