In classical MTS1A, the expression of SV2 isoforms is altered with a marked decrease of SV2A and SV2B paralleling synaptic loss and a selective increase of SV2C in sprouting mossy fibres. These findings suggest a different physiology of sprouting synapses and the possibility to target them with SV2C-specific strategies.

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Objective The cystine/glutamate antiporter system xnormalc− could represent a new target for antiepileptogenic treatments due to its crucial roles in glutamate homeostasis and neuroinflammation. To demonstrate this, we compared epilepsy development and seizure susceptibility in xCT knockout mice (xCT−/−) and in littermate controls (xCT+/+) in different chronic models of epilepsy. Methods Mice were surgically implanted with electrodes in the basolateral amygdala and chronically stimulated to develop self‐sustained status epilepticus (SSSE); continuous video‐electroencephalography monitoring was performed for 28 days after SE and hippocampal histopathology was assessed. Corneal kindling was induced by twice daily electrical stimulation at 6 Hz and maintenance of the fully kindled state was evaluated. Next, messenger RNA (mRNA) and protein levels of xCT and of the proteins involved in the phosphoinositide 3‐kinase (PI3K)/Akt/glycogen synthase kinase 3β (GSK‐3β)/eukaryotic initiation factor 2α (eIF2α)/activating transcription factor 4 (ATF4) signaling pathway were measured at different time points during epileptogenesis in NMRI mice treated with pilocarpine. Finally, the anticonvulsant effect of sulfasalazine (SAS), a nonselective system xnormalc− inhibitor, was assessed against 6 Hz‐evoked seizures in pilocarpine‐treated mice. Results In the SSSE model, xCT−/− mice displayed a significant delayed epileptogenesis, a reduced number of spontaneous recurrent seizures, and less pronounced astrocytic and microglial activation. Moreover, xCT−/− mice showed reduced seizure severity during 6 Hz kindling development and a lower incidence of generalized seizures during the maintenance of the fully kindled state. In pilocarpine‐treated mice, protein levels of the PI3K/Akt/GSK‐3β/eIF2α/ATF4 pathway were increased during the chronic phase of the model, consistent with previous findings in the hippocampus of patients with epilepsy. Finally, repeated administration of SAS protected pilocarpine‐treated mice against acute 6 Hz seizure induction, in contrast to sham controls, in which system xnormalc− is not activated. Significance Inhibition of system xnormalc− could be an attractive target for the development of new therapies with a potential for disease modification in epilepsy.

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