Dataset Information

TAU ablation in excitatory neurons and postnatal TAU knockdown reduce epilepsy, SUDEP, and autism behaviors in a Dravet syndrome model.

ABSTRACT: Intracellular accumulation of TAU aggregates is a hallmark of several neurodegenerative diseases. However, global genetic reduction of TAU is beneficial also in models of other brain disorders that lack such TAU pathology, suggesting a pathogenic role of nonaggregated TAU. Here, conditional ablation of TAU in excitatory, but not inhibitory, neurons reduced epilepsy, sudden unexpected death in epilepsy, overactivation of the phosphoinositide 3-kinase-AKT-mammalian target of rapamycin pathway, brain overgrowth (megalencephaly), and autism-like behaviors in a mouse model of Dravet syndrome, a severe epileptic encephalopathy of early childhood. Furthermore, treatment with a TAU-lowering antisense oligonucleotide, initiated on postnatal day 10, had similar therapeutic effects in this mouse model. Our findings suggest that excitatory neurons are the critical cell type in which TAU has to be reduced to counteract brain dysfunctions associated with Dravet syndrome and that overall cerebral TAU reduction could have similar benefits, even when initiated postnatally.

SUBMITTER: Shao E

PROVIDER: S-EPMC9102397 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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TAU ablation in excitatory neurons and postnatal TAU knockdown reduce epilepsy, SUDEP, and autism behaviors in a Dravet syndrome model.

Shao Eric E Chang Che-Wei CW Li Zhiyong Z Yu Xinxing X Ho Kaitlyn K Zhang Michelle M Wang Xin X Simms Jeffrey J Lo Iris I Speckart Jessica J Holtzman Julia J Yu Gui-Qiu GQ Roberson Erik D ED Mucke Lennart L

Science translational medicine 20220427 642

Intracellular accumulation of TAU aggregates is a hallmark of several neurodegenerative diseases. However, global genetic reduction of TAU is beneficial also in models of other brain disorders that lack such TAU pathology, suggesting a pathogenic role of nonaggregated TAU. Here, conditional ablation of TAU in excitatory, but not inhibitory, neurons reduced epilepsy, sudden unexpected death in epilepsy, overactivation of the phosphoinositide 3-kinase-AKT-mammalian target of rapamycin pathway, bra ...[more]

PMID: 35476595

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Project description:BackgroundSudden unexpected death in epilepsy (SUDEP) is a major cause of death in those with drug-resistant epilepsy (DRE). There is a need for inventories and biomarkers associated with the risk for SUDEP.ObjectiveTo explore the revised SUDEP Risk Inventory (SUDEP-7) in a cohort with DRE and determine the association with Heart Rate and other covariates.MethodsTwenty-five subjects with severe DRE were enrolled in a clinical trial for epilepsy. Baseline demographics, duration of epilepsy, seizure types, seizure frequency, seizure severity, AEDs, and vital signs were collected. Heart rate variability (HRV) was calculated from 1-h recordings of ECG. A SUDEP Risk Inventory (SUDEP-7) was administered, which included seven validated and weighted risk factors initially identified by Walczak et al. as factors associated with SUDEP risk.ResultsThe total score on the revised SUDEP-7 ranged from 1 to 7, mean = 3.4 (SD 1.8). The SUDEP Risk Inventory score was inversely correlated with RMSSD (Pearson r = -0.45, p = 0.027). The following variables were significantly associated with RMSSD: epilepsy duration (p = 0.02), age (p = 0.03), and developmental intellectual disability (p < 0.001). The correlation between RMSSD and SUDEP-7 tended to persist also after the adjustment for patient age (r = -0.40, p = 0.05). Two subjects died of SUDEP: their SUDEP-7 scores were above average and in the upper twenty-fifth and fiftieth percentiles, respectively (6 and 4, mean = 3.4).ConclusionRMSSD, a measure of low frequency HRV, was significantly associated with SUDEP Risk Inventory (SUDEP-7) scores. Using a multivariate model, the covariates of developmental intellectual disability, age, and duration of epilepsy were also significantly associated with decreased HRV. The correlation between decreased HRV and a higher SUDEP-7 score remained unchanged even after the adjustment for patient age. The results suggest that older age, greater duration of epilepsy, and the presence of developmental intellectual disability may increase the risk of SUDEP through their direct influence on decreasing the vagus nerve-mediated HRV. Further validation of the SUDEP-7 inventory is indicated.Trial registrationClinicalTrials.gov, NCT00871377.

Dataset Information

TAU ablation in excitatory neurons and postnatal TAU knockdown reduce epilepsy, SUDEP, and autism behaviors in a Dravet syndrome model.

Publications

TAU ablation in excitatory neurons and postnatal TAU knockdown reduce epilepsy, SUDEP, and autism behaviors in a Dravet syndrome model.

Similar Datasets

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