NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease

Key Points

  • NMDA receptors (NMDARs) are ion channels gated by the excitatory neurotransmitter glutamate. NMDARs are widespread in the CNS and are essential mediators of synaptic transmission and plasticity.

  • NMDARs exist as multiple subtypes that differ in their molecular (subunit) composition. There are assembled as tetramers composed of two obligatory GluN1 subunits along with two GluN2 or GluN3 subunits, of which there are four (GluN2A–GluN2D) and two subtypes (GluN3A and GluN3B) respectively.

  • Each subunit has a typical modular architecture with two large clamshell-like extracellular domains (the N-terminal domain (NTD) involved in assembly and channel modulation and the agonist-binding domain (ABD)), a transmembrane domain (TMD) and a C-terminal domain (CTD) involved in receptor trafficking and signalling. The NTD and CTD regions are the most divergent and account for much of the functional diversity of NMDARs.

  • Each subunit endows the receptor with distinct biophysical, pharmacological and signalling properties

  • The large extracellular region of the receptor harbours an array of binding sites for small-molecule ligands acting as endogenous or exogenous allosteric modulators. Several of these modulators display strong subunit-selectivity, thus allowing for pharmacological profiling of receptor subunit composition.

  • NMDAR subunit composition is plastic, changing during development and according to neuronal activity. Long-term synaptic plasticity of NMDARs also occurs at mature (adult) synapses and has profound consequences on cell firing and subsequent plasticity.

  • Whether specific receptor subtypes carry out specific tasks in the CNS remains a much debated and challenging issue. In particular, evidence points to tri-heteromeric GluN1/GluN2A/GluN2B receptors as critically involved in 'classical' LTP induction at adult CA3–CA1 synapses.

  • NMDARs are implicated in various neurological and psychiatric conditions. Both hypo- and hyperfunction of NMDAR subpopulations can be deleterious, and there is vivid interest in targeting specific subunits for therapeutic interventions.


NMDA receptors (NMDARs) are glutamate-gated ion channels and are crucial for neuronal communication. NMDARs form tetrameric complexes that consist of several homologous subunits. The subunit composition of NMDARs is plastic, resulting in a large number of receptor subtypes. As each receptor subtype has distinct biophysical, pharmacological and signalling properties, there is great interest in determining whether individual subtypes carry out specific functions in the CNS in both normal and pathological conditions. Here, we review the effects of subunit composition on NMDAR properties, synaptic plasticity and cellular mechanisms implicated in neuropsychiatric disorders. Understanding the rules and roles of NMDAR diversity could provide new therapeutic strategies against dysfunctions of glutamatergic transmission.

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Figure 1: NMDAR subunit diversity, structure and expression.
Figure 2: Subunit composition determines receptor properties.
Figure 3: Activity and experience-dependent switch in NMDAR subunit composition.
Figure 4: Plasticity of the NMDAR component at mature synapses.
Figure 5: Role of tri-heteromeric GluN1/GluN2A/GluN2B receptors in AMPAR-mediated synaptic plasticity.
Figure 6: Contribution of NMDAR subunits to Alzheimer's disease and schizophrenia.


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We thank S. Zhu for help with the figures and A. Vergnano for suggestions. We gratefully acknowledge the support of the Agence Nationale pour la Recherche (ANR), the Fondation pour la Recherche Médicale (FRM) and the Swiss National Science Foundation (SNSF).

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Correspondence to Pierre Paoletti.

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Different versions of a given receptor subunit. The term usually refers to different splice forms.

Tri-heteromeric receptors

A class of NMDA receptors that contains three distinct subunits in the tetrameric receptor complex (for example, GluN1/GluN2A/GluN2B receptors).

CA3–CA1 synapses

Excitatory synapses in the hippocampus formed between axons (Schaffer collaterals) of CA3 pyramidal cells and dendrites of CA1 pyramidal cells. NMDA receptor-mediated plasticity (long-term potentiation and long-term depression) has been extensively studied at these synapses.

Allosteric regulation

A form of receptor modulation that involves domains or ligand-binding sites that are distinct from those to which the agonist binds.

Single-channel conductance

The single-channel current divided by the electrical driving force. It refers to the number of charges flowing through a single open channel under a given transmembrane potential and is usually expressed in picoSiemens (10−12 S).

Deactivation kinetics

The time course of the current decrease following agonist removal.

Excitatory postsynaptic cuurent (EPSC) decay

The decay time course of the EPSC. EPSC decay is a key parameter in the control of synaptic integration.

Long-term potentiation

A long-lasting (>1 h) and activity-dependent strengthening of synaptic transmission. It is widely considered to be a major cellular substrate for several forms of learning and memory.

Postsynaptic density

A protein-dense specialization that is attached to the postsynaptic membrane of excitatory synapses. It contains hundreds of proteins, including glutamate receptors, scaffold proteins and signalling molecules.

Critical period

A finite temporal window following birth during which neuronal circuits are shaped; it is characterized by heightened plasticity and experience-dependent remodelling.


A term that refers to the phenomenon whereby previous synaptic activity influences the occurrence of subsequent synaptic plasticity. It is commonly regarded as a mechanism to adjust synaptic plasticity according to the history of the synapse.


A term used to define disorders caused by disruption in synaptic structure and function. Synaptopathy is increasingly seen as a key feature of neurodegenerative and psychiatric diseases.


Cell death induced by excessive extracellular glutamate concentrations.

Negative symptoms

A set of symptoms seen in patients with schizophrenia, including social withdrawal, loss of motivation and reduced affect.

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Paoletti, P., Bellone, C. & Zhou, Q. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci 14, 383–400 (2013). https://doi.org/10.1038/nrn3504

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