MORPHOLOGICAL ALTERATIONS IN NEOCORTICAL AND CEREBELLAR GABAERGIC NEURONS IN A CANINE MODEL OF JUVENILE BATTEN-DISEASE

The pathogenesis of brain dysfunction in a canine model of juvenile Ba tten disease was studied with techniques designed to determine sequent ial changes in mitochondrial morphology and cytochrome oxidase (GO) ac tivity, and in neurons and synapses using gamma-aminobutyric acid (GAB A) as a neurotransmitter. Histochemical and immunocytochemical methods were employed. Mitochondrial alterations were found in a select popul ation of nonpyramidal neurons in neocortex and claustrum, and in cereb ellar basket cells. Proportions of affected neurons at any one time re mained constant over the disease course, with morphologically-abnormal mitochondria first being recognized at age 6 months. Enlarged mitocho ndria were readily identifiable at the light microscope (LM) level as large GO-positive or mitochondrial antibody-positive granular structur es. Colabelling with antibodies to GABA or to parvalbumin (PV) indicat ed that most of these cells were GABAergic. Ultrastructurally, atypica l mitochondria were characterized by globular enlargement, intramitoch ondrial membranous inclusions, and disorganized internal structure. CO activity in all other cell somata and in neuropil was diminished comp ared with normal, age-matched tissue. Glutamic acid decarboxylase (GAD ), PV, and GABA studies demonstrated loss of GABAergic neurons and syn apses in cortex and cerebellum of affected dogs. These results indicat e that abnormal mitochondria are present in neurons in Batten disease, and suggest that suboptimal mitochondrial function may play a role in the pathogenic mechanisms of brain dysfunction in this disorder. (C) 1995 Wiley-Liss, Inc.