Apparent loss and hypertrophy of interneurons in a mouse model of neuronalceroid lipofuscinosis: Evidence for partial response to insulin-like growth factor-1 treatment

The neuronal ceroid lipofuscinoses (NCL) are progressive neurodegenerative disorders with onset from infancy to adulthood that are manifested by blind ness, seizures, and dementia. In NCL, lysosomes accumulate autofluorescent proteolipid in the brain and other tissues. The mnd/mnd mutant mouse was fi rst characterized as exhibiting adult-onset upper and lower motor neuron de generation, but closer examination revealed early, widespread pathology sim ilar to that seen in NCL. We used the autofluorescent properties of accumul ated storage material to map which CNS neuronal populations in the mnd/mnd mouse show NCL-like pathological changes. Pronounced, early accumulation of autofluorescent lipopigment was found in subpopulations of GABAergic neuro ns, including interneurons in the cortex and hippocampus. Staining for phen otypic markers normally present in these neurons revealed progressive loss of staining in the cortex and hippocampus of mnd/mnd mice, with pronounced hypertrophy of remaining detectable interneurons. In contrast, even in aged mutant mice, many hippocampal interneurons retained staining for glutamic acid decarboxylase. Treatment with insulin-like growth factor-1 partially r estored interneuronal number and reduced hypertrophy in some subregions. Th ese results provide the first evidence for the involvement of interneurons in a mouse model of NCL. Moreover, our findings suggest that at least some populations of these neurons persist in a growth factor-responsive state.