Hyperactivity of mTORC1 or mTORC2-dependent signaling causes epilepsy downstream of somatic PTEN loss
Cullen, E. R.; Mittelstadt, I.; Weston, M. C.
Show abstract
Gene variants that hyperactivate PI3K-mTOR signaling in the brain lead to epilepsy and cortical malformations in humans. Some gene variants associated with these pathologies only hyperactivate mTORC1, but others, such as PTEN, PIK3CA, and AKT, hyperactivate both mTORC1- and mTORC2-dependent signaling. Previous work established a key role for mTORC1 hyperactivity in mTORopathies, however, whether mTORC2 hyperactivity contributes is not clear. To test this, we inactivated mTORC1 and/or mTORC2 downstream of early Pten deletion in a new model of somatic Pten loss-of-function (LOF) in the cortex and hippocampus. Spontaneous seizures and epileptiform activity persisted despite mTORC1 or mTORC2 inactivation alone, but inactivating both mTORC1 and mTORC2 simultaneously normalized brain activity. These results suggest that hyperactivity of both mTORC1 and mTORC2 can cause epilepsy, and that targeted therapies should aim to reduce activity of both complexes.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- The role of subicular VIP-expressing interneurons on seizure dynamics in the intrahippocampal kainic acid model of temporal lobe epilepsy 96%
- Spontaneous recurrent seizures in an intra-amygdala kainate microinjection model of temporal lobe epilepsy are differentially sensitive to antiseizure drugs 95%
- Chronic Seizures Induce Sex-Specific Cognitive Deficits with Loss of Presenilin 2 Function 94%
Similar papers in this journal
- Electrobehavioral phenotype and seizure pharmacosensitivity in a novel mouse model of patient-derived SLC6A1 S295L mutation-associated neurodevelopmental epilepsy 96%
- Neuronal Hyperexcitability: A Key to Unravelling Hippocampal Synaptic Dysfunctions in Lafora Disease 96%
- Daily intermittent fasting is an effective multiscale treatment in preclinical models of absence epilepsy 95%
Similar papers in this journal
Similar papers in this journal
- Genetic expression of 4E-BP1 in juvenile mice alleviates mTOR-induced neuronal dysfunction and epilepsy 97%
- Kcnq2/Kv7.2 controls the threshold and bihemispheric symmetry of cortical spreading depolarization 95%
- Excitatory GABAergic signalling is associated with acquired benzodiazepine resistance in status epilepticus 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.