The Role of Astrocyte Activation in Infantile Neuronal Ceroid Lipofuscinosis

Infantile neuronal ceroid lipofuscinoses: INCLs), or Batten Disease, is an inherited neurodegenerative lysosomal storage disorder affecting the central nervous system: CNS) during infancy or childhood. Hallmark pathological changes include accumulation of autofluorescent material, neuronal loss, cortical thinning, and brain atrophy, which ultimately lead to cognitive deficits, motor dysfunction, seizure activity, and blindness. INCL is the result of mutations in the CLN1 gene leading to a deficiency in the lysosomal enzyme, palmitoyl protein thioesterase 1: PPT1). A mouse model of INCL, the PPT1-deficient: PPT1-/-) mouse, was recently created by a targeted disruption in the CLN1 gene. The phenotype of the PPT1-/- mouse is similar to that found in human INCL patients, suggesting the PPT1-/- mouse is an authentic model of INCL. Although the clinical symptoms of disease are well described, the cellular mechanisms underlying these pathological changes and functional deficits remain poorly understood. Therefore, the first goal of this dissertation was to investigate the temporal-spatial progression of disease in a mouse model of INCL. We demonstrated a profound neuronal and glial involvement underlying both physiological and functional deficits. From these studies, we also found the first pathological change observed was the upregulation of glial fibrillary acidic protein: GFAP), a marker of astrocyte activation, in the thalamus, cortex, and cerebellum. Focal regions of GFAP upregulation were an accurate predictor of future sites of neuronal loss. Since astrocyte activation is both helpful and harmful to an injured CNS, the second aim of this dissertation was to investigate the role of astrocyte activation in a mouse model of INCL using the GFAP-/-, Vimentin-/- mice. We demonstrated that astrocyte activation, as defined by GFAP upregulation, plays a protective role in INCL