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Emerging roles of GluN3-containing NMDA receptors in the CNS

Nature Reviews Neuroscience volume 17, pages 623–635 (2016)Cite this article

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Key Points

  • GluN3 subunits (A and B) were the last members of the glutamate receptor subunit family to be cloned. They assemble with GluN1 and GluN2 (A–D) subunits to form tri-heteromeric NMDA receptors (NMDARs). NMDARs containing the GluN3A subunit seem to counteract some of the well-known functions of classical NMDARs (GluN1–GluN2 di-heteromers) in long-term plasticity and synapse development.

  • GluN3A-containing NMDARs are expressed during a narrow temporal window of early postnatal development and have been proposed to play a part in controlling the timing and extent of neural circuit refinements by acting as a 'brake' to prevent the premature strengthening and stabilization of subsets of excitatory synapses. Interactions of the carboxy-terminal domain of GluN3A with a unique set of intracellular partners are required for this function. In addition, GluN3A-containing NMDARs are much less permeable to Ca2+ ions and relatively insensitive to voltage-dependent block by Mg2+ compared with classical NMDARs.

  • GluN3-containing NMDARs might also influence oligodendrocyte maturation and regulate forms of plasticity that are mediated by presynaptic NMDARs.

  • Expression of GluN3A is reactivated in a number of neurological diseases, and emerging evidence suggests a major pathophysiological role of GluN3A in some of them, including Huntington disease, addiction and white matter damage.

  • The therapeutic potential of targeting GluN3A-containing NMDARs or intracellular regulators of their trafficking or signalling is just beginning to be explored but might provide a rational alternative to previously attempted therapies that targeted the more ubiquitous GluN1 or GluN2 subunits.

  • GluN3 subunits can assemble with only GluN1 subunits in heterologous cells to form surface-expressed di-heteromeric receptors that do not bind glutamate and function as excitatory glycine receptors, but the physiological significance of this function is not known.

Abstract

GluN3-containing NMDA receptors (GluN3-NMDARs) are rarer than the 'classical' NMDARs, which are composed solely of GluN1 and GluN2 subunits, and have non-conventional biophysical, trafficking and signalling properties. In the CNS, they seem to have important roles in delaying synapse maturation until the arrival of sensory experience and in targeting non-used synapses for pruning. The reactivation of GluN3A expression at inappropriate ages may underlie maladaptive synaptic rearrangements observed in addiction, neurodegenerative diseases and other major brain disorders. Here, we discuss current evidence for these and other emerging roles for GluN3-NMDARs in the physiology and pathology of the CNS.

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Figure 1: Properties, distribution and expression pattern of GluN3A-NMDARs.
Figure 2: GluN3A-NMDARs in synapse plasticity and maturation.
Figure 3: Activity-dependent regulation of GluN3A-NMDARs and synapse fate.
Figure 4: Signalling pathways mediating the effects of GluN3A-NMDARs.

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Acknowledgements

The authors thank the members of their groups, as well as K. Hansen, C. Bellone and T. Karadottir for valuable discussion, and L. García-Rabaneda and M. Pérez-Otaño for help with the figures. Work in the authors' laboratories is funded by Spanish Ministry of Science grants (CSD2008-00005 to I.P.-O. and SAF2013-48983-R to I.P.-O. and J.F.W.), UTE project CIMA, Marató TV3 Foundation and the Beca Josefina Garre. R.S.L. is funded by the Allen Institute for Brain Science and wishes to thank the Allen Institute founders, P. G. Allen and J. Allen, for their vision, encouragement and support.

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Authors and Affiliations

  1. Cellular Neurobiology and Neurophysiology Laboratory, Center for Applied Medical Research (CIMA) and University of Navarra Medical School, Avda Pio XII 55, Pamplona, 31008, Spain

    Isabel Pérez-Otaño & John F. Wesseling

  2. Instituto de Neurociencias (CSIC-UMH), San Juan de Alicante, 03550, Spain

    Isabel Pérez-Otaño

  3. Allen Institute for Brain Science, Seattle, 98109, Washington, USA

    Rylan S. Larsen

Authors
  1. Isabel Pérez-Otaño
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  3. John F. Wesseling
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Correspondence to Isabel Pérez-Otaño.

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Glossary

Postsynaptic densities

(PSDs). Specializations on excitatory dendritic spines that were originally identified by electron microscopy. They contain glutamate receptors and many associated scaffolding and trafficking proteins that are crucial for excitatory synaptic transmission.

Coincidence detection

A mechanism through which neurons encode information by detecting two nearly simultaneous inputs from distinct sources.

Critical periods

Finite but modifiable developmental time windows during which sensory experience-mediated input provides information that is essential for normal maturation of sensory circuits.

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).

Open probability

The probability of an individual ion channel being in the open state under a given condition, observed as the fraction of the time that an ionic current is flowing. The value can be between 0 and 1.

Epigenetic changes

Changes in phenotype that are driven by changes in the regulation of gene expression or changes in the function of gene products rather than by a change in genotype. Examples of epigenetic events include DNA methylation, X-chromosome inactivation and embryonic pattern formation.

Prepulse inhibition

A reduction in the magnitude of the startle reflex that occurs when an organism is presented with a non-startling stimulus (a prepulse) before being presented with the startling stimulus. Deficits in prepulse inhibition have been observed in patients with schizophrenia as well as in patients with other psychiatric and neurological disorders.

Non-synonymous variants

Coding-DNA variations that result in an altered amino acid sequence.

Periventricular leukomalacia

A form of white matter injury characterized by ischaemia of white matter adjacent to the lateral ventricles. It is the most common cause of ischaemic brain injury in premature infants, leading to motor problems and developmental delays.

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Pérez-Otaño, I., Larsen, R. & Wesseling, J. Emerging roles of GluN3-containing NMDA receptors in the CNS. Nat Rev Neurosci 17, 623–635 (2016). https://doi.org/10.1038/nrn.2016.92

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