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

Abstract

The majority of NMDA receptors (NMDARs) in the brain are composed of 2 GluN1 and 2 GluN2 subunits. The inclusion or exclusion of 1 N-terminal and 2 C-terminal domains of GluN1 results in 8 splicing variants that exhibit distinct temporal and spatial patterns of expression and functional properties. However, previous functional analyses of <i>Grin1</i> variants have been done using heterologous expression and the in vivo function of <i>Grin1</i> splicing is unknown. Here we show that N-terminal splicing of GluN1 has important functions in the maturation of excitatory synapses. The inclusion of exon 5 of <i>Grin1</i> is up-regulated in several brain regions such as the thalamus and neocortex. We find that deletion of <i>Grin1</i> exon 5 disrupts the developmental remodeling of NMDARs in thalamic neurons and the effect is distinct from that of <i>Grin2a</i> (GluN2A) deletion. Deletion of <i>Grin2a</i> or exon 5 of <i>Grin1</i> alone partially attenuates the shortening of NMDAR-mediated excitatory postsynaptic currents (NMDAR-EPSCs) during early life, whereas deletion of both <i>Grin2a</i> and exon 5 of <i>Grin1</i> completely abolishes the developmental change in NMDAR-EPSC decay time. Deletion of exon 5 of <i>Grin1</i> leads to an overproduction of excitatory synapses in layer 5 pyramidal neurons in the cortex and increases seizure susceptibility in adult mice. Our findings demonstrate that N-terminal splicing of GluN1 has important functions in synaptic maturation and neuronal network excitability.