摘要：SummaryTargeted therapies for epilepsies associated with the mTORC1 signaling negative regulator GATOR1 are lacking. NPRL2 is a subunit of the GATOR1 complex and mutations in GATOR1 subunits, includingNPRL2, are associated with epilepsy. To delineate the mechanisms underlying NPRL2-related epilepsies, we created a mouse (Mus musculus) model with neocortical loss ofNprl2. Mutant mice have increased mTORC1 signaling and exhibit spontaneous seizures. They also display abnormal synaptic function characterized by increased evoked and spontaneous EPSC and decreased evoked and spontaneous IPSC frequencies, respectively. Proteomic and metabolomics studies ofNprl2mutants revealed alterations in known epilepsy-implicated proteins and metabolic pathways, including increases in the neurotransmitter, glycine. Furthermore, glycine actions on the NMDA receptor contribute to the electrophysiological and survival phenotypes of these mice. Taken together, in this neuronalNprl2model, we delineate underlying molecular, metabolic, and electrophysiological mechanisms contributing to mTORC1-related epilepsy, providing potential therapeutic targets for epilepsy.Graphical abstractDisplay OmittedHighlights•Neocortical loss ofNprl2leads to mTORC1-dependent seizures and decreased survival•ConditionalNprl2mutants show increased synaptic excitation and decreased inhibition•Neurotransmitter glycine is increased inNprl2mutant neocortex•Glycine actions at NMDA receptor contribute to synaptic and survival phenotypesNeuroscience; Molecular neuroscience; Omics; Metabolomics
