Elsevier

Neuropharmacology

Volume 196, 15 September 2021, 108609
Neuropharmacology

Invited review
NMDA receptor function in inhibitory neurons

https://doi.org/10.1016/j.neuropharm.2021.108609Get rights and content

Highlights

  • NMDA receptors are present in cortical circuits and controlling information flow.

  • Cortical interneurons show variable NMDA receptor function, depending on subtype.

  • Interneuron NMDA receptors control their activation in a synapse specific manner.

  • The role of NMDA receptors in all interneuron types remains to be determined.

Abstract

N-methyl-d-aspartate receptors (NMDARs) are present in the majority of brain circuits and play a key role in synaptic information transfer and synaptic plasticity. A key element of many brain circuits are inhibitory GABAergic interneurons that in themselves show diverse and cell-type-specific NMDAR expression and function. Indeed, NMDARs located on interneurons control cellular excitation in a synapse-type specific manner which leads to divergent dendritic integration properties amongst the plethora of interneuron subtypes known to exist. In this review, we explore the documented diversity of NMDAR subunit expression in identified subpopulations of interneurons and assess the NMDAR subtype-specific control of their function. We also highlight where knowledge still needs to be obtained, if a full appreciation is to be gained of roles played by NMDARs in controlling GABAergic modulation of synaptic and circuit function.

This article is part of the 'Special Issue on Glutamate Receptors – NMDA receptors'.

Introduction

In the 40 years since the publication of Watkins and Evans seminal review (Watkins and Evans, 1981), many aspects of neuronal diversity and function have been defined, giving a deeper understanding of brain function. Of the many mechanisms elucidated in this time, the role of local inhibitory microcircuits formed by GABAergic interneurons (INs) are arguably one of the most powerful mechanisms for information processing and network function in cortical circuits. Whilst we know a great deal about the recruitment of INs to local microcircuits, the role of N-methyl-d-aspartate receptors (NMDARs) remains poorly understood. This is due, in part, to the greater diversity of INs compared to principal cells, but also due to the inherent difficulty in disentangling the physiological role of different NMDAR subtypes (Traynelis et al., 2010; Wyllie et al., 2013). Transgenic approaches targeting NMDARs and INs have provided great insight into their respective function. Indeed, aspects of NMDAR function in INs have been reviewed previously (Akgül and McBain, 2016; Pelkey et al., 2017; Moreau and Kullmann, 2013). However, recent developments such as subunit specific pharmacology, suggest a more diverse function for IN localised NMDARs to circuit function. In this review, we highlight the ability of NMDARs to control the activation of hippocampal INs and the likely ramifications on circuit level inhibition and plasticity.

Section snippets

Functional aspects of NMDAR structure

The detailed structure and function of NMDARs in neurons has been the research focus of a number of research groups and reviewed by others in this special edition, and elsewhere (Wyllie et al., 2013; Cull-Candy et al., 2001; Seeburg et al., 1995; Hansen et al., 2017). However, for the purposes of defining the role of NMDARs in INs, it is pertinent to provide a brief overview here. Native NMDARs in rodents are coded by the genes Grin1-3, which give rise to a variety of proteins which, in the

Anatomical and neurochemical aspects of hippocampal interneuron diversity

Neuronal circuits have long been known to comprise both spiny excitatory glutamatergic neurons and mostly aspiny INs (Cajal, 1911). INs primarily release GABA from their presynaptic terminals, which acts at synaptic and extrasynaptic GABAA and GABAB receptors in mature neurons to hyperpolarise postsynaptic membranes and inhibit presynaptic neurotransmitter release (Fritschy and Panzanelli, 2014; Kulik et al., 2018). INs are located in all hippocampal layers, with somatodendritic axes aligned

Molecular basis for NMDAR expression in interneurons

NMDARs are widely expressed in the brain, with their expression pattern undergoing clear development and region specific patterning. The expression of NMDARs has primarily been based on localisation of RNA or proteins to given cells types, as a proxy for functional receptor expression. However, despite the diversity of IN subtypes, they constitute the minority of neurons (<20% in cortical circuits) and as such their molecular fingerprint is often overlooked in biochemical assays which take into

Functional NMDARs in interneurons

Although there is relatively limited information available on the subtype and compartment-specific localisation of NMDAR subunits to the dendritic membranes of INs, most appear to express mRNA for all neuron specific subtypes (Perszyk et al., 2016). Based on this expression a number of studies have confirmed the presence of functional NMDAR synaptic currents in identified INs. To correlate with mRNA analysis, the summary that follows is organised into NMDAR-mediated responses by neurochemical

NMDAR-dependent effects on cellular and circuit function in interneurons

As we have described above many aspects of NMDAR function in INs of the hippocampus and cortex remain unknown, particularly relating to functional receptor composition and developmental regulation. Nevertheless, local network function relies on these receptors, from the level of the dendrite through to the local circuit, which we will now outline.

Conclusions

In this review, we summarise the recent key findings relating to functional properties of NMDARs in INs of the hippocampus and cortex. We discuss that, while great diversity of NMDAR subunit composition likely exists; only a few studies have addressed the physiological consequences of this feature of the diverse population of inhibitory neurons. Understanding these properties is critical to understanding how local networks appropriately process and store information over a variety of

Declaration of competing interest

The authors state that they have no competing financial interests regarding this work.

Acknowledgements

The authors wish to members of the Wyllie and Kind lab groups for on-going discussions. We acknowledge the generous support for funding of past and on-going research related to the content of this review from: Biotechnology and Biological Sciences Research Council (BB/N015878/10), Medical Research Council (MR/P006213/1), Epilepsy Research UK (P1602), Simons Foundation Autism Research Initiative (SFARI; 529085), The Loulou Foundation, The Patrick Wild Centre, The Shirley Foundation and the R S

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