Profound loss of GABAergic interneurons in the PPT1 knockout mouse model of infantile neuronal ceroid lipofuscinosis

Abstract

Introduction: The neuronal ceroid lipofuscinoses (NCL) are progressive neurodegenerative disorders with onset from infancy to adulthood that are manifested by blindness, seizures and dementia. In infantile NCL (INCL), a mutation in the palmitoyl protein thioesterase (PPT1) gene results in loss of PPT1 activity and lysosomal accumulation of autofluorescent proteolipid in the brain and other tissues. We have generated a PPT1 knockout mouse model of INCL (PPT1–/–) and characterized pathological changes in the CNS of these mice, which die by 8 months of age.Results: 7‐month‐old PPT1–/– exhibited NCL‐like pathology with prominent accumulation of autofluorescent lipopigment throughout the CNS, together with pronounced cerebral atrophy. Staining for phenotypic markers normally present in subpopulations of interneurons in the cortex and hippocampus revealed progressive loss of staining in the cortex and hippocampus, with persisting interneurons exhibiting pronounced hypertrophy and abnormal dendritic morphology.Conclusions: Taken together with our findings in the other mouse models of NCL and preliminary data from NCL patient derived tissue, these results provide further substantive evidence for the involvement of interneurons in the NCLs.Acknowledgements: Supported by The Batten's Disease Support and Research Association, The Natalie Fund, The Remy Fund; Batten's Disease Family Association.