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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.
Highlights
In early postnatal development, the formation and maturation of excitatory synapses play critical roles in the proper wiring of neuronal networks required for learning and memory
The fidelity of this biochemical fractionation was validated by the near absence of membrane proteins in the cytosolic (CYT) fraction; negligible expression of the presynaptic protein, synaptophysin (Syp), in the PSD; absence of the postsynaptic density protein, PSD-95, from the Triton-soluble fraction (TSF); and progressive enrichment of NR1 and PSD-95 from the initial homogenate (PNS) to the PSD (Figure 1b, c)
We tested the hypotheses that (1) NR3A-containing NMDA-type glutamate receptors (NMDARs) shift from a synaptic to a peri-/extrasynaptic location with development, and (2) NR3A suppresses glutamate receptor activity during early life to prevent premature synaptic strengthening and stabilization
Summary
The formation and maturation of excitatory synapses play critical roles in the proper wiring of neuronal networks required for learning and memory. The balance between synapse stabilization and elimination is highly sensitive to changes in the complement of synaptic proteins. NMDAR activation is crucial for synaptic strengthening and weakening [1,2], processes that are pronounced during early life [3,4] and instructive for proper brain development. Unlike most NMDAR subunits, NR3A acts in a novel, dominant-negative manner to limit receptor function and the ability of synapses to strengthen [8,14]. When expressed with NR1 alone, in the absence of NR2 subunits, NR3-NMDARs form a glycine-sensitive cation channel [15,16,17]; these NR1/NR3 channels appear to be expressed in myelin rather than neurons [18]
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