GABAERGIC NEUROAXONAL DYSTROPHY AND OTHER CYTOPATHOLOGICAL ALTERATIONS IN FELINE NIEMANN-PICK DISEASE TYPE-C

Feline Niemann-Pick disease type C (NPC) is an autosomal recessive lys osomal storage disease which shares many of the clinical, biochemical and pathological features of the corresponding human disorder. Cytopat hological alterations in distinct neuronal cell populations were inves tigated in this animal model to gain a better understanding of the pat hogenesis of brain dysfunction, Golgi and immunocytochemical methods w ere employed to characterize the cell architectural changes occurring in neuronal somata, dendrites and axons at different stages of disease progression. Cortical pyramidal neurons in laminae II, III, and V exh ibited various degrees of meganeurite and/or swollen axon hillock form ation with or without ectopic dendritogenesis. Enlarged axon hillock r egions with neuritic processes and spines were recognized early in the progression of feline NPC but were less prevalent in mid to late stag es of the disease. Glutamic acid decarboxylase (GAD) immunocytochemist ry demonstrated immunoreactive spheroids in numerous GABAergic axons i n neocortex, subcortical areas, and cerebellum. Parvalbumin-immunoreac tive axonal spheroid distribution in brain closely mirrored results fr om the GAD studies, whereas calbindin D-28k-immunoreactive spheroids w ere conspicuously absent in most cortical and subcortical areas examin ed. Purkinje cell axonal spheroid formation progressed in a distal to proximal direction, with eventual involvement of recurrent axon collat erals. Purkinje cell death and a concomitant decrease in the numbers o f spheroids in the cerebellum were observed late in the disease course . Clinical neurological signs in feline NPC occur in parallel with neu ronal structural alterations and suggest that GABAergic neuroaxonal dy strophy is a contributor to brain dysfunction in this disease.