The most frequent genetic cause of focal epilepsies is variations in the GATOR1 (GAP activity toward RAGs 1) complex genes DEPDC5, NPRL2, and 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. While 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 mTORC1 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.
 

JOURNAL： Human molecular genetics

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

DOI：https://doi.org/10.1093/hmg/ddab337