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Yet, for most LSDs, including CLN3 disease, the most common form of childhood dementia, it is unclear what mechanisms drive neurologic symptoms. Do deficits arise from loss of function of the mutated protein or toxicity from storage accumulation? Here, using in vitro voltage-sensitive dye imaging and in vivo electrophysiology, we find progressive hippocampal dysfunction occurs before notable lysosomal storage and neuronal loss in 2 CLN3 disease mouse models. Pharmacologic reversal of lysosomal storage deposition in young mice does not rescue this circuit dysfunction. Additionally, we find that CLN3 disease mice lose an electrophysiologic marker of new memory encoding \u2014 hippocampal sharp-wave ripples. This discovery, which is also seen in Alzheimer\u2019s disease, suggests the possibility of a shared electrophysiologic signature of dementia. Overall, our data describe new insights into previously unknown network-level changes occurring in LSDs affecting the central nervous system and highlight the need for new therapeutic interventions targeting early circuit defects.<\/jats:p>","DOI":"10.1172\/jci.insight.131961","type":"journal-article","created":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T12:01:16Z","timestamp":1569931276000},"source":"Crossref","is-referenced-by-count":30,"title":["Neuronal network dysfunction precedes storage and neurodegeneration in a lysosomal storage disorder"],"prefix":"10.1172","volume":"4","author":[{"given":"Rebecca C.","family":"Ahrens-Nicklas","sequence":"first","affiliation":[{"name":"Division of Human Genetics, Department of Pediatrics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Tecedor","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory 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