Mtor Complexes in Epilepsy and Seizure Disorders
Abstract number :
3.051
Submission category :
1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year :
2022
Submission ID :
2204800
Source :
www.aesnet.org
Presentation date :
12/5/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:26 AM
Authors :
James Okoh, BS – Baylor College of Medicine, Houston, Texas, USA; Jacqunae Mays, B.S. – Neuroscience – Baylor College of Medicine, Houston, Texas, USA; Alexandre Bacq, Ph.D. – Sorbonne University, Paris Brain Institute (ICM) , INSERM, CNRS, AP-HP, Pitié-Salpêtrière Hospital, Paris, France.; Hongyi Zhou, M.S. – Neuroscience – Baylor College of Medicine, Houston, Texas, USA; Khalel Imanbeyev, MD – Neuroscience – Baylor College of Medicine, Houston, Texas, USA; Paymaan Jafar-Nejad, Ph.D. – Ionis Pharmaceuticals; Jeffrey Noebels, Ph.D., MD – Neurology – Baylor College of Medicine, Houston, Texas, USA; Stephanie Baulac, Ph.D. – Sorbonne University, Paris Brain Institute (ICM) , INSERM, CNRS, AP-HP, Pitié-Salpêtrière Hospital, Paris, France.; Mauro Costa-Mattioli, Ph.D. – Neuroscience – Baylor College of Medicine, Houston, Texas, USA
Rationale: Dysregulation of the mammalian target of rapamycin (mTOR), which functions via two distinct complexes named mTORC1 and mTORC2, has been causally linked to epilepsy. Currently, it is widely believed that hyperactivation of mTORC1, which is sensitive to the drug rapamycin, leads to abnormal network rhythmicity associated with epilepsy. Most of the evidence supporting the role for hyperactivation of mTORC1 in epilepsy relies on its chronic pharmacological inhibition with rapamycin. However, chronic rapamycin treatment, which reduces seizures in several epilepsy models, also inhibits mTORC2. We recently found that genetic inhibition of mTORC2, but not mTORC1, improved behavioral and neurophysiological deficits (including seizures) in mice lacking the mTOR upstream negative regulator, Pten. Thus, it remains unclear whether hyperactivation of mTORC1 or mTORC2 leads to abnormal synchronized neuronal firing during epilepsy.
Methods: To dissect the role of mTOR complexes in epilepsy, we used molecular genetics to selectively silence the activity of either mTORC1 or mTORC2 in forebrain neurons. Using the Cre-lox system, we selectively deleted Rptor (encoding the mTORC1-defining component, Raptor) and Rictor (encoding the mTORC2-defining component, Rictor) to inhibit mTORC1 and mTORC2, respectively. Next, we examined both behavioral and electrographic seizures in the kainic acid (KA) model, which is one of the most widely studied epilepsy models in the field.
Results: We found that KA activated mTORC2 more persistently than mTORC1. Surprisingly, we found that genetic inhibition of mTORC1 increased acute KA-induced seizures while genetic inhibition of mTORC2 reduced acute KA-induced seizures.
Conclusions: Our results indicate that the mTOR complexes may play distinct roles in seizure generation. More importantly, future studies in other epilepsy and seizure models can help stratify seizures into mTOR-complex-specific subspectra and could inform more effective therapeutic strategies.
Funding: R01 NS124145
Basic Mechanisms