Neuromotor alterations and cerebellar deficits in aged arylsulfatase A-deficient transgenic mice

Arylsulfatase A (ASA)-deficient (-/-) mice and ASA(+/+) controls were const ructed as a transgenic model for the lysosomal storage disease, metachromat ic leukodystrophy (MLD). One-year-old ASA(-/-) mice showed impaired rotarod performance and altered walking pattern characterized by a shorter pace, l ater evolving into more severe ataxia with tremor in 2-year-old mice. Exami nation of cerebellar histology showed that 2-year-old ASA(-/-) mice have lo st most of the calbindin immunoreactivity from their Purkinje cell dendrite s and show simplified dendritic architecture. Additionally, ASA-deficient m ice lost a substantial proportion of their Purkinje cells. Recordings of un itary potentials and stimulation of climbing fibers on cerebellar slices fr om 2-year-old mice indicated that, although the main cerebellar synapses se em to be present and functioning physiologically, the climbing fibers of AS A-deficient mice may have enhanced effects on Purkinje cell activity. It is concluded that ambulatory dysfunctions in ASA(-/-) mice might be explained by an imbalance in the consequences of climbing fiber signals upon Purkinj e cell activity due to selective neurodegeneration within the cerebellum. ( C) 1999 Elsevier Science Ireland Ltd. All rights reserved.