Batten's disease is an inherited neurological disorder affecting humans and also has been documented in a variety of animal species including dogs and sheep. Individuals with this disorder are characterized by normal appearance at birth, followed by insidiously progressive neurological deterioration including retarded mental development and/or dementia, blindness, movement disorders, and seizures. Death is the in- evitable outcome as no treatment is currently available. Only recently has research progress begun to clarify the metabolic basis for this disease in that massive storage of a single protein (subunit c of mitochondrial ATP-synthase) has been established. This finding suggests that Batten's disease is a proteolipid proteinosis, but the primary enzyme defect awaits determination. Furthermore, changes in brain structure and function set in motion by the primary metabolic defect and that lead to the devastating neurological symptoms also are poorly understood. Our goal in these studies is to use a well documented animal model of Batten's disease, canine neuronal ceroid lipofuscinosis, to explore mechanisms of pathogenesis. We have proposed two alternative hypotheses to explain onset and progression of neuronal dysfunction. Based on the observation that cortical GABAergic neurons contain more mitochondria than other cortical neurons, coupled with identification of a mitochondrial enzyme as the major storage product in this disease, we propose that GABAergic neurons are inherently more susceptible to the primary metabolic defect (Hypothesis I). According to this view, early GABAergic cell loss would be predicted to precede pyramidal cell loss, but the ensuing loss of inhibitory function would later accelerate pyramidal cell dysfunction. Alternatively, brain dysfunction in Batten's disease may be due to the same mechanisms believed critical in neuronal storage diseases known to be caused by lysosomal hydrolase defects (Hypothesis II). In these cases ectopic dendrites and associated synaptic connections, axonal spheroids in GABAergic neurons, and alterations in second messenger systems are believed linked to specific aspects of brain dysfunction. We propose to use state-of-the-art electrophysiologic and morphologic techniques to explore these hypotheses. A greater understanding of the mechanisms of brain dysfunction in Batten's e anticipated to give insight not only into the primary metabolic defect in brain, but also into possible ways to treat and/or ameliorate clinical symptoms.
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