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 Grin1 variants have been done using heterologous expression and the in vivo function of Grin1 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 Grin1 is up-regulated in several brain regions such as the thalamus and neocortex. We find that deletion of Grin1 exon 5 disrupts the developmental remodeling of NMDARs in thalamic neurons and the effect is distinct from that of Grin2a (GluN2A) deletion. Deletion of Grin2a or exon 5 of Grin1 alone partially attenuates the shortening of NMDAR-mediated excitatory postsynaptic currents (NMDAR-EPSCs) during early life, whereas deletion of both Grin2a and exon 5 of Grin1 completely abolishes the developmental change in NMDAR-EPSC decay time. Deletion of exon 5 of Grin1 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.

Glutamatergic dysfunction precedes neuron loss in cerebral organoids withMAPTmutation

“…This splicing change is consistent with an excitatory phenotype, because expression of this exon leads to slower desensitization of AMPA receptors, increasing susceptibility to excitotoxicity (Koike et al, 2000; Pei et al, 2009). We also identified increased exclusion of GRIN1 exon 5 in tau-V337M organoids, which has been associated with the overproduction of excitatory synapses in layer V pyramidal neurons in adult mice that in turn increases seizure susceptibility (Liu et al, 2019), and may contribute to the cortical layer vulnerability observed in our model and in FTD brain.…”

MeCP2 gates spatial learning-induced alternative splicing events in the mouse hippocampus

“…Interestingly, the Grin1 gene gives rise to 8 splice variants and recently it has been shown that the selective expression of different GluN1 isoforms determines long-term potentiation in the hippocampus and spatial memory performance [ 67 ]. Moreover, the relative abundance of some spliced isoforms of GluN1 subunit is associated with increased seizure susceptibility in adult mice [ 68 ]. Taken together, these findings suggest that altered alternative splicing events observed in MeCP2-shRNA mice at baseline might impact proper neuronal function and consequently contribute to cognitive deficits and excitation/inhibition imbalance reminiscent of RTT.…”

Alternative splicing of GluN1 gates glycine-primed internalization of NMDA receptors

“…GluN1 splice variants are differentially expressed in various types of neurons, across different brain regions, and throughout distinct development stages [6][7][8][9]. N-terminal splicing affects NMDAR channel gating kinetics [10][11][12], as well as modulation by pH, Zn 2+ , extracellular polyamines [13] and long-term synaptic potentiation [14]. Many important properties of NMDA receptors such as glycine and glutamate potency, and voltage-dependent blockade by Mg 2+ are unaffected by the presence of N1 insert [4,5,15].…”