N-terminal alternative splicing of GluN1 regulates the maturation of excitatory synapses and seizure susceptibility

The GluN1 subunit of NMDA receptors has multiple splice variants with distinct temporal and spatial expression patterns. The in vivo function of GluN1 splice variants is unknown. Here we provide evidence that N-terminal splicing of GluN1 regulates developmental remodeling of synaptic NMDA receptors and maturation of excitatory synapses. Using mice carrying a deletion of the exon 5 of Grin1, we show that the inclusion of the N-terminal cassette of GluN1 shortens the time course of NMDA receptor-mediated excitatory synaptic currents in the thalamus and cortex. Deletion of Grin1 exon 5 causes an overproduction of excitatory synapses in the cortex of young mice and an increase in seizure susceptibility in adult mice.