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Remodeled cortical inhibition prevents motor seizures in generalized epilepsy
Author(s) -
Jiang Xiao,
LupienMeilleur Alexis,
Tazerart Sabrina,
Lachance Mathieu,
Samarova Elena,
Araya Roberto,
Lacaille JeanClaude,
Rossignol Elsa
Publication year - 2018
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25301
Subject(s) - parvalbumin , epilepsy , neuroscience , ganglionic eminence , gabaergic , biology , inhibitory postsynaptic potential
Objective Deletions of CACNA1A , encoding the α1 subunit of Ca V 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 Nkx2.1 Cre ;Cacna1a c/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 PV Cre ;Cacna1a c/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 PV Cre ;Cacna1a c/c mice display reduced cortical perisomatic inhibition and frequent absences but only rare motor seizures. Compared to Nkx2.1 Cre ;Cacna1a c/c mice, PV Cre ;Cacna1a c/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