Remodeled cortical inhibition prevents motor seizures in generalized epilepsy
- PMID: 30048010
- DOI: 10.1002/ana.25301
Remodeled cortical inhibition prevents motor seizures in generalized epilepsy
Abstract
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.
© 2018 American Neurological Association.
Comment in
-
Double agent mTOR.Epilepsy Curr. 2019 Jan;19(1):44-46. doi: 10.1177/1535759718822033. Epub 2019 Jan 30. Epilepsy Curr. 2019. PMID: 30838925 Free PMC article.
Similar articles
-
Double agent mTOR.Epilepsy Curr. 2019 Jan;19(1):44-46. doi: 10.1177/1535759718822033. Epub 2019 Jan 30. Epilepsy Curr. 2019. PMID: 30838925 Free PMC article.
-
CaV 2.1 ablation in cortical interneurons selectively impairs fast-spiking basket cells and causes generalized seizures.Ann Neurol. 2013 Aug;74(2):209-22. doi: 10.1002/ana.23913. Epub 2013 Jul 1. Ann Neurol. 2013. PMID: 23595603 Free PMC article.
-
Reversing frontal disinhibition rescues behavioural deficits in models of CACNA1A-associated neurodevelopment disorders.Mol Psychiatry. 2021 Dec;26(12):7225-7246. doi: 10.1038/s41380-021-01175-1. Epub 2021 Jun 14. Mol Psychiatry. 2021. PMID: 34127816
-
Involvement of cortical fast-spiking parvalbumin-positive basket cells in epilepsy.Prog Brain Res. 2016;226:81-126. doi: 10.1016/bs.pbr.2016.04.012. Epub 2016 Jun 7. Prog Brain Res. 2016. PMID: 27323940 Free PMC article. Review.
-
[GABAergic mechanisms in generalized epilepsies: the neuroanatomical dimension].Rev Neurol (Paris). 1997;153 Suppl 1:S8-13. Rev Neurol (Paris). 1997. PMID: 9686242 Review. French.
Cited by
-
Developing a pathway to clinical trials for CACNA1A-related epilepsies: A patient organization perspective.Ther Adv Rare Dis. 2024 Apr 25;5:26330040241245725. doi: 10.1177/26330040241245725. eCollection 2024 Jan-Dec. Ther Adv Rare Dis. 2024. PMID: 38681799 Free PMC article. Review.
-
Unraveling the Neural Circuits: Techniques, Opportunities and Challenges in Epilepsy Research.Cell Mol Neurobiol. 2024 Mar 6;44(1):27. doi: 10.1007/s10571-024-01458-5. Cell Mol Neurobiol. 2024. PMID: 38443733 Free PMC article. Review.
-
Interneuron odyssey: molecular mechanisms of tangential migration.Front Neural Circuits. 2023 Sep 14;17:1256455. doi: 10.3389/fncir.2023.1256455. eCollection 2023. Front Neural Circuits. 2023. PMID: 37779671 Free PMC article. Review.
-
Treadmill exercise improves hippocampal neural plasticity and relieves cognitive deficits in a mouse model of epilepsy.Neural Regen Res. 2024 Mar;19(3):657-662. doi: 10.4103/1673-5374.377771. Neural Regen Res. 2024. PMID: 37721298 Free PMC article.
-
mTORC1-mediated acquisition of reward-related representations by hippocampal somatostatin interneurons.Mol Brain. 2023 Jul 3;16(1):55. doi: 10.1186/s13041-023-01042-w. Mol Brain. 2023. PMID: 37400913 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Miscellaneous