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Updated: May 6, 2026
Induction of Protein Deletion Through In Utero Electroporation to Define Deficits in Neuronal Migration in Transgenic Models
Published on: January 12, 2015
Focal DEPDC5 loss without disruption to cerebral cortical neuron migration recapitulates DEPDC5-related focal
Karenna J Groff1, Yini Liang1, Christopher Morici1
1F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Abstract:
Focal cortical dysplasia (FCD) is a major cause of refractory epilepsy and is associated with pathogenic variants in mTOR pathway genes, including DEPDC5, the most common cause of familial focal epilepsy. The mechanisms of epileptogenesis associated with FCD and hyperactive mTOR signaling remain unclear in DEPDC5-related epilepsy. To test whether DEPDC5 loss leading to seizures requires in utero cortical developmental defects or whether postnatal neuronal dysfunction of mTORC1 is sufficient to drive seizures, we developed a postnatal focal cortical Depdc5-knockout mouse model. Postnatal day 0-1 Depdc5-floxed mice received unilateral motor cortex injections of either AAV-Cre-GFP or control AAV-GFP. The AAV-Cre-GFP-injected hemisphere had decreased DEPDC5 levels with hyperactivation of mTOR that increased with age compared with both the contralateral hemisphere and the AAV-GFP-injected mice. Cortical lamination was not disrupted by postnatal DEPDC5 loss. Pathologic hallmarks of FCDs were identified in the Depdc5-knockout hemisphere, including increased SMI-311 neurofilament staining, hypomyelination, astrogliosis, and microglial activation. Mice with postnatal cortical DEPDC5 loss exhibited lower seizure thresholds, increased focal seizures, and increased rates of seizure-induced death compared with control mice. This study demonstrates that postnatal DEPDC5 loss and subsequent mTOR hyperactivation without disruption of cortical migration is sufficient to cause epilepsy.
Insights
Postnatal DEPDC5 loss causes focal cortical dysplasia (FCD) and epilepsy by hyperactivating the mTOR pathway. This occurs without disrupting cortical development, proving postnatal dysfunction is sufficient for seizure development.
Area of Science:
- Neuroscience
- Genetics
- Epilepsy Research
Background:
- Focal cortical dysplasia (FCD) is a leading cause of refractory epilepsy.
- Pathogenic variants in mTOR pathway genes, notably DEPDC5, are linked to FCD and familial focal epilepsy.
- Mechanisms connecting DEPDC5 mutations, mTOR signaling, and epileptogenesis in FCD remain unclear.
Purpose of the Study:
- To determine if DEPDC5 loss-induced seizures require prenatal developmental defects or if postnatal mTORC1 dysfunction is sufficient.
- To investigate the role of DEPDC5 in epileptogenesis through a postnatal knockout mouse model.
Main Methods:
- Developed a postnatal focal cortical Depdc5-knockout mouse model using AAV-Cre-GFP injection in P0-1 Depdc5-floxed mice.
- Assessed DEPDC5 levels, mTORC1 activity, cortical lamination, and pathological FCD hallmarks.
- Evaluated seizure thresholds, seizure frequency, and seizure-induced mortality.
Main Results:
- Postnatal DEPDC5 loss led to decreased DEPDC5 levels and age-dependent mTORC1 hyperactivation in the targeted hemisphere.
- Cortical lamination remained intact, but FCD hallmarks (neurofilament accumulation, hypomyelination, astrogliosis, microglial activation) emerged.
- Mice exhibited reduced seizure thresholds, increased focal seizures, and higher seizure-induced death rates.
Conclusions:
- Postnatal DEPDC5 loss and subsequent mTOR hyperactivation are sufficient to cause epilepsy.
- Disruption of cortical development is not required for DEPDC5-related epileptogenesis.
- This model elucidates the role of postnatal mTORC1 dysregulation in FCD-associated epilepsy.
