Abstract 2005 Poster Session II, Sunday, 5/2 (poster 233)

The neuronal ceroid lipofuscinoses (NCL) are progressive degenerative disorders with onset from infancy to adulthood that are manifested by blindness, seizures and dementia. The development of an animal model that recapitulates the clinical and pathological features of NCL represents an initial step towards discovering underlying disease mechanisms and testing potential therapeutic strategies. The characteristics pathological hallmark of the NCLs is the lysosomal accumulation of autofluorescent proteolipid in the brain and other tissues. We have examined populations of affected neurons in the CNS of mnd and nclf mutant mice which show such NCL-like pathology. Pronounced, early accumulation of autofluorescent lipopigment was found in subpopulations of GABAergic neurons, including interneurons in the cortex and hippocampus of both mnd and nclf mice. Staining for phenotypic markers normally present in these neurons revealed progressive loss of interneuronal staining in the cortex and hippocampus. This apparent loss was evident in both mutants, but progressed more slowly in nclf mice. Both mutant strains exhibited pronounced atrophy of remaining detectable interneurons and disrupted dendritic morphology. However, even in aged mutant mice of either strain, many hippocampal interneurons retained staining for more essential markers of their neurotransmitter function. Remarkably, treatment of aged mnd mice with insulin-like growth factor 1 (IGF-1) partially restored interneuronal number and reduced hypertrophy in some sub-regions. These results provide the first evidence for the involvement of interneurons in mouse models of NCL. Moreover, our findings suggest that at least some populations of these neurons persist in a growth factor-responsive state that is amenable to therapeutic intervention. It will be very informative to extend these studies to mice carrying null-mutations in the genes associated with NCL, as these animals become available.

(Supported by The Batten's Disease Support and Research Association, The Natalie Fund, The Remy Fund, Children's Brain Diseases Foundation).