{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T19:34:30Z","timestamp":1790192070057,"version":"4.1.0"},"reference-count":56,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2024,5,8]],"date-time":"2024-05-08T00:00:00Z","timestamp":1715126400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Genetic variations in proteins of the mechanistic target of rapamycin (mTOR) pathway cause a spectrum of neurodevelopmental disorders often associated with brain malformations and with intractable epilepsy. The mTORopathies are characterized by hyperactive mTOR pathway and comprise tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type II. How hyperactive mTOR translates into abnormal neuronal activity and hypersynchronous network remains to be better understood. Previously, the role of upregulated GluN2C\u2010containing glutamate\u2010gated N\u2010methyl\u2010D\u2010aspartate receptors (NMDARs) has been demonstrated for germline defects in the <jats:italic>TSC<\/jats:italic> genes. Here, we questioned whether this mechanism would expand to other mTORopathies in the different context of a somatic genetic variation of the MTOR protein recurrently found in FCD type II.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used a rat model of FCD created by in utero electroporation of neural progenitors of dorsal telencephalon with expression vectors encoding either the wild\u2010type or the pathogenic <jats:italic>MTOR<\/jats:italic> variant (p.S2215F). In this mosaic configuration, patch\u2010clamp whole\u2010cell recordings of the electroporated, spiny stellate neurons and extracellular recordings of the electroporated areas were performed in neocortical slices. Selective inhibitors were used to target mTOR activity and GluN2C\u2010mediated currents.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Neurons expressing the mutant protein displayed an excessive activation of GluN2C NMDAR\u2010mediated spontaneous excitatory postsynaptic currents. GluN2C\u2010dependent increase in spontaneous spiking activity was detected in the area of electroporated neurons in the mutant condition and was restricted to a critical time window between postnatal days P9 and P20.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Somatic <jats:italic>MTOR<\/jats:italic> pathogenic variant recurrently found in FCD type II resulted in overactivation of GluN2C\u2010mediated neuronal NMDARs in neocortices of rat pups. The related and time\u2010restricted local hyperexcitability was sensitive to subunit GluN2C\u2010specific blockade. Our study suggests that GluN2C\u2010related pathomechanisms might be shared in common by mTOR\u2010related brain disorders.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.18000","type":"journal-article","created":{"date-parts":[[2024,5,8]],"date-time":"2024-05-08T14:53:26Z","timestamp":1715180006000},"page":"2111-2126","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Pathogenic <scp><i>MTOR<\/i><\/scp> somatic variant causing focal cortical dysplasia drives hyperexcitability via overactivation of neuronal <scp>GluN2C<\/scp> N\u2010methyl\u2010D\u2010aspartate receptors"],"prefix":"10.1111","volume":"65","author":[{"given":"Louison","family":"Pineau","sequence":"first","affiliation":[{"name":"Institut de Neurobiologie de la M\u00e9diterran\u00e9e, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale Aix\u2010Marseille University  Marseille 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