Synaptic and Extrasynaptic NMDA Receptors Are Gated by Different Endogenous Coagonists

Abstract

N-methyl-d-aspartate receptors (NMDARs) are located in neuronal cell membranes at synaptic and extrasynaptic locations, where they are believed to mediate distinct physiological and pathological processes. Activation of NMDARs requires glutamate and a coagonist whose nature and impact on NMDAR physiology remain elusive. We report that synaptic and extrasynaptic NMDARs are gated by different endogenous coagonists, d-serine and glycine, respectively. The regionalized availability of the coagonists matches the preferential affinity of synaptic NMDARs for d-serine and extrasynaptic NMDARs for glycine. Furthermore, glycine and d-serine inhibit NMDAR surface trafficking in a subunit-dependent manner, which is likely to influence NMDARs subcellular location. Taking advantage of this coagonist segregation, we demonstrate that long-term potentiation and NMDA-induced neurotoxicity rely on synaptic NMDARs only. Conversely, long-term depression requires both synaptic and extrasynaptic receptors. Our observations provide key insights into the operating mode of NMDARs, emphasizing functional distinctions between synaptic and extrasynaptic NMDARs in brain physiology.

Morphological plasticity of astroglia: Understanding synaptic microenvironment

“…Thus, such receptors could be “strategically” positioned to respond strongly to any small changes in astroglial coverage of the synapse. Re‐arrangement of such a complex synaptic microenvironment during use‐dependent astroglial changes might also contribute to the differential action of two NMDARs co‐agonists, glycine and d ‐serine, depending on the intra‐ or extrasynaptic receptor location (Papouin et al, 2012). Finally, it is logical to think that volumetric changes in perisynaptic astroglia are capable of physically altering the local environment, restricting or permitting molecular signal exchange among its various components.…”

Organization, control and function of extrasynaptic NMDA receptors

“…In hippocampal CA1 pyramidal neurons of adult rats, GluN2B-NMDARs were shown to be absent at synapses, but could still be found at extrasynaptic locations [19]. However, the replacement of GluN2B-with GluN2A-NMDARs at synapses is not ubiquitous and complete, and GluN2B-NMDARs still represent a major portion of synaptic NMDARs in many other regions of the adult central nervous system (CNS) [16,54] as reviewed in [9].…”

“…Interestingly, the difference in the co-agonist used by NMDARs at synaptic and extrasynaptic sites appears primarily to be based on the fact that D-serine is released at synapses and that the activity of glial glycine transporter 1 (GlyT1) prevents glycine from accessing the synaptic cleft [19]. Thus, the delineation between synaptic and extrasynaptic space, with regard to the co-agonist control of NMDARs, seems to be defined by D-serine and glycine abundance.…”

“…The identity of the second agonist, termed coagonist, was elusive until recently, even though glycine was originally shown to bind to the co-agonist site [67][68][69]. In the CA1 region of the adult rat hippocampus, it was demonstrated recently that D-serine is the endogenous co-agonist of synaptic NMDARs, but that glycine gates the extrasynaptic NMDARs that mediate the tonic current and contribute to the response induced by exogenous application of NMDA [19]. SICs were not investigated in this study and whether NMDARs that mediate SICs are also gated by glycine, or by D-serine, is still unknown.…”

Disk-Shaped Amperometric Enzymatic Biosensor for in Vivo Detection of d-serine

“…1,2 NMDARs, a member of the glutamate receptor family, play an especially important role in basal synaptic transmission and as a critical mediator of many forms of synaptic plasticity. 3,4 They have also been important clinical therapeutic targets in psychiatric disorders such as schizophrenia and depression, 5,6 as well as neurodegenerative disorders like Huntington's disease 7 and amyotrophic lateral sclerosis (ALS).…”