Invited reviewNMDA receptor function in inhibitory neurons
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
References (116)
- et al.
Disinhibition in learning and memory circuits: new vistas for somatostatin interneurons and long-term synaptic plasticity
Brain Res. Bull.
(2018) Postsynaptic GABABRs inhibit L-type calcium channels and abolish long-term potentiation in hippocampal somatostatin interneurons
Cell Rep.
(2018)- et al.
NMDA receptor subunits: diversity, development and disease
Curr. Opin. Neurobiol.
(2001) Submillisecond AMPA receptor-mediated signaling at a principal neuron–interneuron synapse
Neuron
(1997)Distinct modes of AMPA receptor suppression at developing synapses by GluN2A and GluN2B: single-cell NMDA receptor subunit deletion in vivo
Neuron
(2011)- et al.
The Yin and Yang of NMDA receptor signalling
Trends Neurosci.
(2003) Critical period plasticity is disrupted in the barrel cortex of FMR1 knockout mice
Neuron
(2010)NMDA receptor ablation on parvalbumin-positive interneurons impairs hippocampal synchrony, spatial representations, and working memory
Neuron
(2010)- et al.
Differential distribution and function of GABABRs in somato-dendritic and axonal compartments of principal cells and interneurons in cortical circuits
Neuropharmacology
(2018) - et al.
LTP and LTD in cortical GABAergic interneurons: emerging rules and roles
Neuropharmacology
(2011)
Distinct NMDA receptors provide differential modes of transmission at mossy fiber-interneuron synapses
Neuron
In developing hippocampal neurons, NR2B-containing NMDA receptors can mediate signalling to neuronal survival and synaptic potentiation, as well as neuronal death
Neuroscience
mGluR5 and NMDA receptors drive the experience-and activity-dependent NMDA receptor NR2B to NR2A subunit switch
Neuron
Developmental and regional expression in the rat brain and functional properties of four NMDA receptors
Neuron
NMDA receptor-dependent function and plasticity in inhibitory circuits
Neuropharmacology
Large variability in synaptic n-methyl-d-aspartate receptor density on interneurons and a comparison with pyramidal-cell spines in the rat hippocampus
Neuroscience
Region-specific expression of NMDA receptor GluN2C subunit in parvalbumin-positive neurons and astrocytes: analysis of GluN2C expression using a novel reporter model
Neuroscience
Functional distinctions between spine and dendritic synapses made onto parvalbumin-positive interneurons in mouse cortex
Cell Rep.
NMDA receptor-mediated dendritic spikes and coincident signal amplification
Curr. Opin. Neurobiol.
Expression of NMDAR2D glutamate receptor subunit mRNA in neurochemically identified interneurons in the rat neostriatum, neocortex and hippocampus
Mol. Brain Res.
Expression of NMDA glutamate receptor subunit mRNAs in neurochemically identified projection and interneurons in the striatum of the rat
Mol. Brain Res.
Diverse roles for ionotropic glutamate receptors on inhibitory interneurons in developing and adult brain
J. Physiol.
Facilitating pyramid to horizontal oriens-alveus interneurone inputs: dual intracellular recordings in slices of rat hippocampus
J. Physiol.
Neurogliaform and ivy cells: a major family of nNOS expressing GABAergic neurons
Front. Neural Circ.
Schaffer collateral and perforant path inputs activate different subtypes of NMDA receptors on the same CA1 pyramidal cell
Br. J. Pharmacol.
The entorhinal cortical alvear pathway differentially excites pyramidal cells and interneuron subtypes in hippocampal CA1
Cerebr. Cortex
Parvalbumin cell ablation of NMDA-R1 causes increased resting network excitability with associated social and self-care deficits
Neuropsychopharmacology
Morphological diversity and connectivity of hippocampal interneurons
Cell Tissue Res.
KCTD12 auxiliary proteins modulate kinetics of GABAB receptor-mediated inhibition in cholecystokinin-containing interneurons
Cerebr. Cortex
Altered dendritic spine function and integration in a mouse model of fragile X syndrome
Nat. Commun.
Dendritic discrimination of temporal input sequences in cortical neurons
Science
Physiological properties of anatomically identified basket and bistratified cells in the CA1 area of the rat hippocampus in vitro
Hippocampus
Histologie du syste me nerveux de I'Homme et des verte be s
Maloine (Paris)
Dendritic calcium nonlinearities switch the direction of synaptic plasticity in fast-spiking interneurons
J. Neurosci.
Afferent specific role of NMDA receptors for the circuit integration of hippocampal neurogliaform cells
Nat. Commun.
Activity-dependent tuning of intrinsic excitability in mouse and human neurogliaform cells
Elife
Dendritic NMDA receptors in parvalbumin neurons enable strong and stable neuronal assemblies
Elife
New insights into the classification and nomenclature of cortical GABAergic interneurons
Nat. Rev. Neurosci.
GluN2D-containing NMDA receptors-mediate synaptic currents in hippocampal interneurons and pyramidal cells in juvenile mice
Front. Cell. Neurosci.
NR2A subunit expression shortens NMDA receptor synaptic currents in developing neocortex
J. Neurosci.
Spiny and non-spiny parvalbumin-positive hippocampal interneurons show different plastic properties
Cell Rep.
Distinct laminar requirements for NMDA receptors in experience-dependent visual cortical plasticity
Cerebr. Cortex
Connectivity and network state-dependent recruitment of long-range VIP-GABAergic neurons in the mouse hippocampus
Nat. Commun.
Interneurons of the hippocampus
Hippocampus
GABAA receptors and plasticity of inhibitory neurotransmission in the central nervous system
Eur. J. Neurosci.
Fractional Ca2+ currents through somatic and dendritic glutamate receptor channels of rat hippocampal CA1 pyramidal neurones
J. Physiol.
Mechanism of differential control of NMDA receptor activity by NR2 subunits
Nature
Distinct timing in the activity of cannabinoid-sensitive and cannabinoid-insensitive basket cells
Nat. Neurosci.
Integrated morphoelectric and transcriptomic classification of cortical GABAergic cells
Cell
Total number and ratio of excitatory and inhibitory synapses converging onto single interneurons of different types in the CA1 area of the rat hippocampus
J. Neurosci.
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