Neuronal network dysfunction precedes storage and neurodegeneration in a lysosomal storage disorder
Rebecca C. Ahrens-Nicklas, Luis Tecedor, Arron F. Hall, Elena Lysenko, Akiva S. Cohen, Beverly L. Davidson, Eric D. Marsh
Rebecca C. Ahrens-Nicklas, Luis Tecedor, Arron F. Hall, Elena Lysenko, Akiva S. Cohen, Beverly L. Davidson, Eric D. Marsh
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Research Article Metabolism Neuroscience

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.

Authors

Rebecca C. Ahrens-Nicklas, Luis Tecedor, Arron F. Hall, Elena Lysenko, Akiva S. Cohen, Beverly L. Davidson, Eric D. Marsh

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Figure 7

Like AD mouse models, late-stage CLN3–/– mice have fewer SWRs than WT. Ripples that do occur trigger an exaggerated gamma frequency response.

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Like AD mouse models, late-stage CLN3–/– mice have fewer SWRs than WT. R...
(A) Quantification of SWRs per 30-minute recording from the hippocampal EEGs of WT (shown in black) and CLN3–/– (shown in red) mice reveals decreased SWR abundance in CLN3–/– mice. Group sizes in A: WT n = 118 thirty-minute recordings, N = 7 mice; CLN3–/– n = 142 thirty-minute recordings, N = 7 mice. Bar graphs show mean ± SEM and SWR number from all recordings; black points show mean SWR abundance for each mouse. Statistical analysis was completed 2 ways (Mann-Whitney U test comparing the SWR number between all WT and CLN3–/– recording periods and 2-way ANOVA to capture variation because of both individual mice and genotype); both demonstrated a difference between genotypes with ****P < 0.0001. (B and C) Average spectrogram of the 1 second surrounding SWRs detected in WT and CLN3–/– hippocampus shows that in WT animals there is a brief increase in power in the ripple frequency band (150–250 Hz), while in CLN3–/– animals there is a prolonged increase in power in multiple frequency bands. (D) Peak power in the low gamma range after an SWR is increased in CLN3–/– mice as compared with WT. (E) Gamma power is increased in CLN3–/– (red) mice for several hundred milliseconds surrounding the peak SWR as compared with WT (black) (2-way ANOVA followed by Holm-Šídák multiple-comparisons test). Group sizes for D and E: WT n = 2059 SWRs, N = 7 mice; CLN3–/– n = 1363 SWRs, N = 7 mice. Bar graphs show mean ± SEM gamma power from all SWRs; black points show mean peak gamma power during SWRs by mouse. Statistical analysis was completed 2 ways: Mann-Whitney U testing comparing peak gamma power in all WT and CLN3–/– SWRs gave ****P < 0.0001; while 2-way ANOVA to capture variation because of both individual mice and genotype showed a genotype effect with *P = 0.03. (F) In CLN3–/– hippocampus, the cumulative fraction of SWRs triggering a high-power gamma frequency response increases with disease progression from 6 months (solid line, WT n = 1334 SWRs, CLN3–/– n = 2040 SWRs, N = 4 mice/genotype), to 11 months (large dashed line, WT n = 1114 SWRs, CLN3–/– n = 833 SWRs, N = 4 mice/genotype), to 18 months (small dashed line, WT n = 947 SWRs, CLN3–/– n = 942 SWRs, N = 3 mice/genotype).