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4E-BP1 expression in embryonic postmitotic neurons mitigates mTORC1-induced cortical malformations and behavioral
Lena H Nguyen1,2, Manas Sharma2, Angelique Bordey2
1Department of Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, United States.
Abstract:
Hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway during neurodevelopment leads to focal cortical malformations associated with intractable seizures. Recent evidence suggests that dysregulated cap-dependent translation downstream of mTORC1 contributes to cytoarchitectural abnormalities and seizure activity. Here, we examined whether reducing cap-dependent translation by expressing a constitutively active form of the translational repressor, 4E-BP1, downstream of mTORC1 would prevent the development of cortical malformations and seizures. 4E-BP1CA was expressed embryonically either in radial glia (neural progenitor cells) that generate cortical layer 2/3 pyramidal neurons or in migrating neurons destined to layer 2/3 using a conditional expression system. In both conditions, 4E-BP1CA expression reduced mTORC1-induced neuronal hypertrophy and alleviated cortical mislamination, but a subset of ectopic neurons persisted in the deep layers and the white matter. Despite the above improvements, 4E-BP1CA expression in radial glia had no effects on seizure frequency and further exacerbated behavioral seizure severity associated with mTORC1 hyperactivation. In contrast, conditional 4E-BP1CA expression in migratory neurons mitigated the severity of behavioral seizures but the seizure frequency remained unchanged. These findings advise against targeting 4E-BPs by 4E-BP1CA expression during embryonic development for seizure prevention and suggest the presence of a development-dependent role for 4E-BPs in mTORC1-induced epilepsy.
Insights
Targeting cap-dependent translation via 4E-BP1 activation during development did not prevent seizures in mTORC1-related cortical malformations. This approach may worsen seizure severity, suggesting a complex role for 4E-BPs in epilepsy.
Area of Science:
- Neuroscience
- Developmental Biology
- Molecular Biology
Background:
- Hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway is linked to neurodevelopmental disorders, specifically focal cortical malformations and intractable seizures.
- Dysregulated cap-dependent translation downstream of mTORC1 is implicated in cytoarchitectural abnormalities and seizure generation.
Purpose of the Study:
- To investigate if reducing cap-dependent translation by expressing a constitutively active form of 4E-BP1 (4E-BP1CA) can prevent mTORC1-induced cortical malformations and seizures during embryonic development.
Main Methods:
- Conditional expression of 4E-BP1CA in radial glia or migrating neurons destined for cortical layer 2/3 during embryonic development.
- Assessment of neuronal hypertrophy, cortical cytoarchitecture, and seizure activity (frequency and severity).
Main Results:
- 4E-BP1CA expression reduced mTORC1-induced neuronal hypertrophy and cortical mislamination in both radial glia and migrating neuron models.
- Despite architectural improvements, ectopic neurons persisted, and 4E-BP1CA expression in radial glia exacerbated seizure severity without affecting frequency.
- Conditional expression in migratory neurons mitigated seizure severity but did not alter seizure frequency.
Conclusions:
- Targeting 4E-binding proteins (4E-BPs) via 4E-BP1CA expression during embryonic development is not recommended for preventing seizures associated with mTORC1-driven cortical malformations.
- These findings highlight a potential development-dependent role for 4E-BPs in mTORC1-induced epilepsy, suggesting therapeutic strategies need careful temporal consideration.
