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The most frequent genetic cause of focal epilepsies is variations in the GAP activity toward RAGs 1 complex genes DEP domain containing 5 ( DEPDC5 ), nitrogen permease regulator 2-like protein ( NPRL2 ) and nitrogen permease regulator 3-like protein ( NPRL3 ). Because these variations are frequent and associated with a broad spectrum of focal epilepsies, a unique pathology categorized as GATORopathy can be conceptualized. Animal models recapitulating the clinical features of patients are essential to decipher GATORopathy. Although several genetically modified animal models recapitulate  DEPDC5 -related epilepsy, no models have been reported for  NPRL2 - or  NPRL3 -related epilepsies. Here, we conditionally deleted  Nprl2  and  Nprl3  from the dorsal telencephalon in mice [ Emx1  cre/+ ;  Nprl2  f/f  ( Nprl2 -cKO) and  Emx1  cre/+ ;  Nprl3  f/f  ( Nprl3 -cKO)] and compared their phenotypes with  Nprl2  +/ −  ,  Nprl3  +/ −   and  Emx1  cre/+ ;  Depdc5  f/f  ( Depdc5 -cKO) mice.  Nprl2 -cKO and  Nprl3 -cKO mice recapitulated the major abnormal features of patients—spontaneous seizures, and dysmorphic enlarged neuronal cells with increased mechanistic target of rapamycin complex 1 signaling—similar to  Depdc5 -cKO mice. Chronic postnatal rapamycin administration dramatically prolonged the survival period and inhibited seizure occurrence but not enlarged neuronal cells in  Nprl2 -cKO and  Nprl3 -cKO mice. However, the benefit of rapamycin after withdrawal was less durable in  Nprl2 - and  Nprl3 -cKO mice compared with  Depdc5 -cKO mice. Further studies using these conditional knockout mice will be useful for understanding GATORopathy and for the identification of novel therapeutic targets.

Dorsal telencephalon-specific Nprl2 - and Nprl3 -knockout mice: novel mouse models for GATORopathy