ArticleHuman molecular genetics2020
Prevention of premature death and seizures in a Depdc5 mouse epilepsy model through inhibition of mTORC1.
Article in Human molecular genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 43 citations in OpenAlex.
- Mosaic human cortical organoids model mTOR-related focal cortical dysplasia through DEPDC5 deletion.Brain : a journal of neurology · 2026Article
- Article
- Early death and neuronal abnormalities inbioRxiv : the preprint server for biology · 2025Article
- Focal DEPDC5 loss without disruption to cerebral cortical neuron migration recapitulates DEPDC5-related focal epilepsy.JCI insight · 2025Article
- Emerging Role of Tripartite Synaptic Transmission in the Pathomechanism of Autosomal-Dominant Sleep-Related Hypermotor Epilepsy.International journal of molecular sciences · 2025Review
- DEPDC5 regulates the strength of excitatory synaptic transmission by interacting with ubiquitin-specific protease 46.Neurobiology of disease · 2025Article
- mTOR pathway diseases: challenges and opportunities from bench to bedside and the mTOR node.Orphanet journal of rare diseases · 2025Review
- Review
- Spotlight on mechanism of sudden unexpected death in epilepsy in Dravet syndrome.Translational psychiatry · 2025Review
- Neuronal cell type specific roles for Nprl2 in neurodevelopmental disorder-relevant behaviors.Neurobiology of disease · 2025Article
- Ragopathies and the rising influence of RagGTPases on human diseases.Nature communications · 2024Review
- Targeted suppression of mTORC2 reduces seizures across models of epilepsy.Nature communications · 2023Article
- Sudden Unexpected Death in Epilepsy and Respiratory Defects in a Mouse Model of DEPDC5-Related Epilepsy.Annals of neurology · 2023Article
- Targeting the biology of aging with mTOR inhibitors.Nature aging · 2023Review
- Clocking Epilepsies: A Chronomodulated Strategy-Based Therapy for Rhythmic Seizures.International journal of molecular sciences · 2023Review
- 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
- Cardiac Investigations in Sudden Unexpected Death in DEPDC5-Related Epilepsy.Annals of neurology · 2022Article
- Imaging Genetics in Epilepsy: Current Knowledge and New Perspectives.Frontiers in molecular neuroscience · 2022Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Mutations in DEP domain containing 5 (DEPDC5) are increasingly appreciated as one of the most common causes of inherited focal epilepsy. Epilepsies due to DEPDC5 mutations are often associated with brain malformations, tend to be drug-resistant, and have been linked to an increased risk of sudden unexplained death in epilepsy (SUDEP). Generation of epilepsy models to define mechanisms of epileptogenesis remains vital for future therapies. Here, we describe a novel mouse model of Depdc5 deficiency with a severe epilepsy phenotype, generated by conditional deletion of Depdc5 in dorsal telencephalic neuroprogenitor cells. In contrast to control and heterozygous mice, Depdc5-Emx1-Cre conditional knockout (CKO) mice demonstrated macrocephaly, spontaneous seizures and premature death. Consistent with increased mTORC1 activation, targeted neurons were enlarged and both neurons and astrocytes demonstrated increased S6 phosphorylation. Electrophysiologic characterization of miniature inhibitory post-synaptic currents in excitatory neurons was consistent with impaired post-synaptic response to GABAergic input, suggesting a potential mechanism for neuronal hyperexcitability. mTORC1 inhibition with rapamycin significantly improved survival of CKO animals and prevented observed seizures, including for up to 40 days following rapamycin withdrawal. These data not only support a primary role for mTORC1 hyperactivation in epilepsy following homozygous loss of Depdc5, but also suggest a developmental window for treatment which may have a durable benefit for some time even after withdrawal.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.