Remodeled cortical inhibition prevents motor seizures in generalized epilepsy
| Autor: | Roberto Araya, Mathieu Lachance, Jean-Claude Lacaille, Elsa Rossignol, Xiao Jiang, Elena Samarova, Alexis Lupien-Meilleur, Sabrina Tazerart |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Mutation Ataxia Ganglionic eminence Transgene Biology medicine.disease_cause medicine.disease 03 medical and health sciences Epilepsy 030104 developmental biology 0302 clinical medicine Neurology medicine GABAergic Neurology (clinical) medicine.symptom Generalized epilepsy Neuroscience 030217 neurology & neurosurgery PI3K/AKT/mTOR pathway |
| Zdroj: | Annals of Neurology. 84:436-451 |
| ISSN: | 0364-5134 |
| Popis: | Objective Deletions of CACNA1A, encoding the α1 subunit of CaV 2.1 channels, cause epilepsy with ataxia in humans. Whereas the deletion of Cacna1a in γ-aminobutyric acidergic (GABAergic) interneurons (INs) derived from the medial ganglionic eminence (MGE) impairs cortical inhibition and causes generalized seizures in Nkx2.1Cre ;Cacna1ac/c mice, the targeted deletion of Cacna1a in somatostatin-expressing INs (SOM-INs), a subset of MGE-derived INs, does not result in seizures, indicating a crucial role of parvalbumin-expressing (PV) INs. Here we identify the cellular and network consequences of Cacna1a deletion specifically in PV-INs. Methods We generated PVCre ;Cacna1ac/c mutant mice carrying a conditional Cacna1a deletion in PV neurons and evaluated the cortical cellular and network outcomes of this mutation by combining immunohistochemical assays, in vitro electrophysiology, 2-photon imaging, and in vivo video-electroencephalographic recordings. Results PVCre ;Cacna1ac/c mice display reduced cortical perisomatic inhibition and frequent absences but only rare motor seizures. Compared to Nkx2.1Cre ;Cacna1ac/c mice, PVCre ;Cacna1ac/c mice have a net increase in cortical inhibition, with a gain of dendritic inhibition through sprouting of SOM-IN axons, largely preventing motor seizures. This beneficial compensatory remodeling of cortical GABAergic innervation is mTORC1-dependent and its inhibition with rapamycin leads to a striking increase in motor seizures. Furthermore, we show that a direct chemogenic activation of cortical SOM-INs prevents motor seizures in a model of kainate-induced seizures. Interpretation Our findings provide novel evidence suggesting that the remodeling of cortical inhibition, with an mTOR-dependent gain of dendritic inhibition, determines the seizure phenotype in generalized epilepsy and that mTOR inhibition can be detrimental in epilepsies not primarily due to mTOR hyperactivation. Ann Neurol 2018;84:436-451. |
| Databáze: | OpenAIRE |
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