Genetic Deletion of NR3A Accelerates Glutamatergic Synapse Maturation

Abstract

Glutamatergic synapse maturation is critically dependent upon activation of NMDA-type glutamate receptors (NMDARs); however, the contributions of NR3A subunit-containing NMDARs to this process have only begun to be considered. Here we characterized the expression of NR3A in the developing mouse forebrain and examined the consequences of NR3A deletion on excitatory synapse maturation. We found that NR3A is expressed in many subcellular compartments, and during early development, NR3A subunits are particularly concentrated in the postsynaptic density (PSD). NR3A levels dramatically decline with age and are no longer enriched at PSDs in juveniles and adults. Genetic deletion of NR3A accelerates glutamatergic synaptic transmission, as measured by AMPAR-mediated postsynaptic currents recorded in hippocampal CA1. Consistent with the functional observations, we observed that the deletion of NR3A accelerated the expression of the glutamate receptor subunits NR1, NR2A, and GluR1 in the PSD in postnatal day (P) 8 mice. These data support the idea that glutamate receptors concentrate at synapses earlier in NR3A-knockout (NR3A-KO) mice. The precocious maturation of both AMPAR function and glutamate receptor expression are transient in NR3A-KO mice, as AMPAR currents and glutamate receptor protein levels are similar in NR3A-KO and wildtype mice by P16, an age when endogenous NR3A levels are normally declining. Taken together, our data support a model whereby NR3A negatively regulates the developmental stabilization of glutamate receptors involved in excitatory neurotransmission, synaptogenesis, and spine growth.

Specific Roles of NMDA Receptor Subunits in Mental Disorders

“…The GluN3A subunit makes NMDA receptor ion channels less Ca 2+ -permeable and Mg 2+ -insensitive [36]. In the absence of GluN3A, the expression of markers of synaptic maturation is accelerated [37]. Enhanced responses of NMDA receptors and increased number of dendritic spines are observed in early stage of postnatal cerebrocortical neurons [38], and inducing long-term potentiation (LTP) at young synapses is easier [39].…”

“…The overexpression of GluN3A retards synaptic maturation and attenuates LTP at adult synapses [39]. These data indicate that GluN3A acts as a molecular brake to limit the plasticity and maturation of excitatory synapses [34, 37] and may have a profound impact on several functional/behavioral activities in adult animals [40] (Table 1 ).…”

Structure-based discovery of antagonists for GluN3-containing N-methyl-d-aspartate receptors

“…The GluN3 subunits appears to function as modulatory subunits that reduce the susceptibility of NMDA receptors to Mg 2+ -blockage and reduce Ca 2+ -permeability (Cavara et al, 2010; Chatterton et al, 2002; Pérez-Otaño et al, 2001; Sasaki et al, 2002). Furthermore, GluN3 subunits are involved in synapse maturation (Das et al, 1998; Henson et al, 2012; Pérez-Otaño et al, 2006; Roberts et al, 2009), synaptic plasticity (Larsen et al, 2011), and are neuroprotective in various cells (Káradóttir et al, 2005; Martínez-Turrillas et al, 2012; Micu et al, 2006; Nakanishi et al, 2009; Salter and Fern, 2005). Consequently, the GluN3 subunits could be promising new targets for therapeutic intervention in neuropathological conditions that include excitotoxicity and cognitive impairment (Cavara and Hollmann, 2008; Henson et al, 2010; Stys and Lipton, 2007).…”

GluN3A expression restricts spine maturation via inhibition of GIT1/Rac1 signaling

“…During the refinement stage, NMDARs additionally contain GluN3A subunits that serve as a brake on synapse maturation and stabilization, which might provide a counterbalance to limit synapse numbers. Supporting this idea, loss of GluN3A increases spine density and size (7) and accelerates the expression of markers of synaptic maturation (8), whereas overexpression reduces synapse and spine density and yields a higher proportion of smaller, immature spines (9). However, the downstream mechanisms by which GluN3A inhibits synapse and spine maturation remain unknown.…”