Double agent mTOR

Remodeled Cortical Inhibition Prevents Motor Seizures in Generalized Epilepsy Jiang X, Lupien-Meilleur A, Tazerart S, Lachance M, Samarova E, Araya R, Lacaille JC, Rossignol E. Ann Neurol. 2018 Sep;84(3):436-451.

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.

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.

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 mechanistic target of rapamycin complex 1 (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.

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.