OBJECTIVE: Excitatory neuronal homeostasis is crucial for neuronal survival, circuit function, and plasticity. Disruptions in this form of homeostasis are believed to underpin a variety of neuronal conditions including intellectual disability, epilepsy, and autism. However, the underlying genetic and molecular mechanisms maintaining this homeostasis remain poorly understood. Biallelic recurrent loss of function mutations in METHODS: Through multiple lines of inquiry, we establish that C12ORF57/GRCC10 plays an unexpected central role in synaptic homeostatic downscaling in response to elevated activity, uncovering a novel mechanism for neuronal excitatory homeostasis. To probe these mechanisms, we developed a new knockout (KO) mouse model of the gene's murine ortholog, INTERPRETATION: Our study suggests through this novel mechanism, deletion of Grcc10 disrupts the characteristic synaptic AMPA receptor downscaling that accompanies increased activity in glutamatergic neurons.