SIK3 controls synaptic localization of NMDA receptors by phosphorylating GluN1

Synaptic NMDA-type glutamate receptors (NMDARs) are central components of all neural computations. NMDAR levels critically vary between synapses but how the synaptic localization of NMDARs is controlled remains unclear. Here we show that SIK3, a serine-threonine protein kinase, localizes to synapses where it phosphorylates the obligatory NMDAR subunit GluN1 at a single site. This single phosphorylation event controls NMDAR recruitment to synapses. Genetic deletion of SIK3 severely and selectively decreases synaptic GluN1 levels by ~60% without altering AMPA-type glutamate receptor levels or inducing major transcriptional changes. Pharmacological inhibition of SIK3 impairs synaptic NMDAR responses within 45 minutes. Mutating the SIK3-phosphorylation site inhibits GluN1 synaptic recruitment. 'Sleepy', a gain-of-function mutation in SIK3 that increases sleep, selectively enhances synaptic NMDAR levels by increasing GluN1 phosphorylation. Thus, SIK3 phosphorylation of GluN1 provides a key signal for recruiting NMDARs to synapses.