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Increased glycine contributes to synaptic dysfunction and early mortality in Nprl2 seizure model.

ABSTRACT: Targeted 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, including NPRL2, are associated with epilepsy. To delineate the mechanisms underlying NPRL2-related epilepsies, we created a mouse (Mus musculus) model with neocortical loss of Nprl2. 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 of Nprl2 mutants 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 neuronal Nprl2 model, we delineate underlying molecular, metabolic, and electrophysiological mechanisms contributing to mTORC1-related epilepsy, providing potential therapeutic targets for epilepsy.

SUBMITTER: Dentel B

PROVIDER: S-EPMC9118754 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Increased glycine contributes to synaptic dysfunction and early mortality in Nprl2 seizure model.

Dentel Brianne B Angeles-Perez Lidiette L Ren Chongyu C Jakkamsetti Vikram V Holley Andrew J AJ Caballero Daniel D Oh Emily E Gibson Jay J Pascual Juan M JM Huber Kimberly M KM Tu Benjamin P BP Tsai Peter T PT

iScience 20220429 5

Targeted 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, including NPRL2, are associated with epilepsy. To delineate the mechanisms underlying NPRL2-related epilepsies, we created a mouse (Mus musculus) model with neocortical loss of Nprl2. Mutant mice have increased mTORC1 signaling and exhibit spontaneous seizures. They also display abnormal synap ...[more]

PMID: 35602938

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Increased glycine contributes to synaptic dysfunction and early mortality in Nprl2 seizure model.

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Increased glycine contributes to synaptic dysfunction and early mortality in Nprl2 seizure model.

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