Abstract
Biallelic recurrent loss of function mutations in C12ORF57, a novel open reading frame, underlie Temtamy syndrome (TS)-a neurodevelopmental disorder characterized by dysgenesis of the corpus callosum, epilepsy, and severe intellectual disability. Investigate the function of this gene, we used a knockout (KO) mouse model of its murine ortholog, Grcc10. Grcc10 KO mice exhibit the characteristic phenotypic features seen in human TS patients, including increased epileptiform activity. Corresponding with this seizure susceptibility, hippocampal neurons in these mice exhibited significantly increased AMPA receptor expression levels and higher amplitude of miniature excitatory postsynaptic currents (mEPSCs). We also find that GRCC10/C12ORF57 modulates the activity of calcium/calmodulin dependent kinase 4 (CAMK4) and regulates the expression of CREB and ARC, which are involved in the synaptic scaling of AMPA receptors. Through multiple lines of inquiry, we establish that C12ORF57/GRCC10 plays a central modulatory role in synaptic homeostasis and uncover a novel mechanism for neuronal excitatory tuning.