Dataset Information

Neuronal network dysfunction precedes storage and neurodegeneration in a lysosomal storage disorder.

ABSTRACT: Accumulation of lysosomal storage material and late-stage neurodegeneration are hallmarks of lysosomal storage disorders (LSDs) affecting the brain. 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 - hippocampal sharp-wave ripples. This discovery, which is also seen in Alzheimer's 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.

SUBMITTER: Ahrens-Nicklas RC

PROVIDER: S-EPMC6948765 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Neuronal network dysfunction precedes storage and neurodegeneration in a lysosomal storage disorder.

Ahrens-Nicklas Rebecca C RC Tecedor Luis L Hall Arron F AF Lysenko Elena E Cohen Akiva S AS Davidson Beverly L BL Marsh Eric D ED

JCI insight 20191101 21

Accumulation of lysosomal storage material and late-stage neurodegeneration are hallmarks of lysosomal storage disorders (LSDs) affecting the brain. 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 hi ...[more]

PMID: 31573978

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Project description:Cognitive dysfunction is a salient feature of Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). The onset of dementia reflects the spread of Lewy pathology throughout forebrain structures. The mere presence of Lewy pathology, however, provides limited indication of cognitive status. Thus, it remains unclear whether Lewy pathology is the de facto substrate driving cognitive dysfunction in PD and DLB. Through application of α-synuclein fibrils in vivo , we sought to examine the influence of pathologic inclusions on cognition. Following stereotactic injection of α-synuclein fibrils within the mouse forebrain, we measured the burden of α-synuclein pathology at 1-, 3-, and 6-months post-injection within subregions of the hippocampus and cortex. Under this paradigm, the hippocampal CA2/3 subfield was especially susceptible to α- synuclein pathology. Strikingly, we observed a drastic reduction of pathology in the CA2/3 subfield across time-points, consistent with the consolidation of α-synuclein pathology into dense somatic inclusions followed by neurodegeneration. Silver-positive degenerating neurites were observed prior to neuronal loss, suggesting that this might be an early feature of fibril-induced neurotoxicity and a precursor to neurodegeneration. Critically, mice injected with α-synuclein fibrils developed progressive deficits in spatial learning and memory. These findings support that the formation of α-synuclein inclusions in the mouse forebrain precipitate neurodegenerative changes that recapitulate features of Lewy-related cognitive dysfunction.HighlightsMice injected with α-synuclein fibrils develop hippocampal and cortical α- synuclein pathology with a dynamic regional burden at 1-, 3-, and 6-months post-injection.Silver-positive neuronal processes are an early and enduring degenerative feature of the fibril model, while extensive neurodegeneration of the hippocampal CA2/3 subfield is detected at 6-months post-injection.Mice exhibit progressive hippocampal-dependent spatial learning and memory deficits.Forebrain injection of α-synuclein fibrils may be used to model aspects of Lewy-related cognitive dysfunction.

Dataset Information

Neuronal network dysfunction precedes storage and neurodegeneration in a lysosomal storage disorder.

Publications

Neuronal network dysfunction precedes storage and neurodegeneration in a lysosomal storage disorder.

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