ArticleHuman molecular genetics2019
Chronic mTORC1 inhibition rescues behavioral and biochemical deficits resulting from neuronal Depdc5 loss in mice.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 51 citations in OpenAlex.
- Focal DEPDC5 loss without disruption to cerebral cortical neuron migration recapitulates DEPDC5-related focal epilepsy.JCI insight · 2025Article
- DEPDC5 regulates the strength of excitatory synaptic transmission by interacting with ubiquitin-specific protease 46.Neurobiology of disease · 2025Article
- Neuronal cell type specific roles for Nprl2 in neurodevelopmental disorder-relevant behaviors.Neurobiology of disease · 2025Article
- Identifying the Pathogenicity of a Novel NPRL3 Missense Mutation Using Personalized Cortical Organoid Model of Focal Cortical Dysplasia.Journal of molecular neuroscience : MN · 2024Article
- GATOR1 Mutations Impair PI3 Kinase-Dependent Growth Factor Signaling Regulation of mTORC1.International journal of molecular sciences · 2024Article
- Pathogenic genes implicated in sleep-related hypermotor epilepsy: a research progress update.Frontiers in neurology · 2024Review
- The Single-Dose Application of Interleukin-4 Ameliorates Secondary Brain Damage in the Early Phase after Moderate Experimental Traumatic Brain Injury in Mice.International journal of molecular sciences · 2023Article
- Rapamycin improves social and stereotypic behavior abnormalities induced by pre-mitotic neuronal subset specific Pten deletion.Genes, brain, and behavior · 2023Article
- Targeting the biology of aging with mTOR inhibitors.Nature aging · 2023Review
- Involvement of mTOR pathway in neurodegeneration in NSF-related developmental and epileptic encephalopathy.Human molecular genetics · 2023Article
- Modeling genetic mosaicism of the mammalian target of rapamycin pathway in the cerebral cortex.Frontiers in mammal science · 2023Article
- Clinical phenotypic and genotypic characterization ofFrontiers in neurology · 2023Article
- NPRL3 loss alters neuronal morphology, mTOR localization, cortical lamination and seizure threshold.Brain : a journal of neurology · 2022Article
- DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting.Cell reports · 2022Article
- Increased glycine contributes to synaptic dysfunction and early mortality in Nprl2 seizure model.iScience · 2022Article
- Dorsal telencephalon-specific Nprl2- and Nprl3-knockout mice: novel mouse models for GATORopathy.Human molecular genetics · 2022Article
- Prospects and hot spots for mammalian target of rapamycin in the field of neuroscience from 2002 to 2021.Frontiers in integrative neuroscience · 2022Article
- Cardiac Investigations in Sudden Unexpected Death in DEPDC5-Related Epilepsy.Annals of neurology · 2022Article
- Factors influencing the acute pentylenetetrazole-induced seizure paradigm and a literature review.Annals of clinical and translational neurology · 2021Review
- Precision Therapy for Epilepsy Related to Brain Malformations.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2021Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
DEPDC5 is now recognized as one of the genes most often implicated in familial/inherited focal epilepsy and brain malformations. Individuals with pathogenic variants in DEPDC5 are at risk for epilepsy, associated neuropsychiatric comorbidities and sudden unexplained death in epilepsy. Depdc5flox/flox-Syn1Cre (Depdc5cc+) neuronal-specific Depdc5 knockout mice exhibit seizures and neuronal mTORC1 hyperactivation. It is not known if Depdc5cc+ mice have a hyperactivity/anxiety phenotype, die early from terminal seizures or whether mTOR inhibitors rescue DEPDC5-related seizures and associated comorbidities. Herein, we report that Depdc5cc+ mice were hyperactive in open-field testing but did not display anxiety-like behaviors on the elevated-plus maze. Unlike many other mTOR-related models, Depdc5cc+ mice had minimal epileptiform activity and rare seizures prior to seizure-induced death, as confirmed by video-EEG monitoring. Treatment with the mTORC1 inhibitor rapamycin starting after 3 weeks of age significantly prolonged the survival of Depdc5cc+ mice and partially rescued the behavioral hyperactivity. Rapamycin decreased the enlarged brain size of Depdc5cc+ mice with corresponding decrease in neuronal soma size. Loss of Depdc5 led to a decrease in the other GATOR1 protein levels (NPRL2 and NPRL3). Rapamycin failed to rescue GATOR1 protein levels but rather rescued downstream mTORC1 hyperactivity as measured by phosphorylation of S6. Collectively, our data provide the first evidence of behavioral alterations in mice with Depdc5 loss and support mTOR inhibition as a rational therapeutic strategy for DEPDC5-related epilepsy in humans.
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