Dendritic NMDA receptors in parvalbumin neurons enable strong and stable neuronal assemblies

Abstract

Parvalbumin-expressing (PV+) GABAergic interneurons mediate feedforward and feedback inhibition and have a key role in gamma oscillations and information processing. The importance of fast synaptic recruitment, action potential initiation and repolarization, and rapid synchronous GABA release by PV+ cells is well established. In contrast, the functional significance of PV+ cell NMDA receptors (NMDARs), which generate relatively slow postsynaptic currents, is unclear. Underlining their importance, several studies implicate PV+ cell NMDAR disruption in impaired network function and circuit pathologies. Here, we show that dendritic NMDARs underlie supralinear integration of feedback excitation from local pyramidal neurons onto mouse CA1 PV+ cells. Furthermore, by incorporating NMDARs at feedback connections onto PV+ cells in spiking networks, we show that these receptors enable cooperative recruitment of PV+ interneurons, strengthening and stabilising principal cell assemblies. Failure of this phenomenon provides a parsimonious explanation for cognitive and sensory gating deficits in pathologies with impaired PV+ NMDAR signalling.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Jonathan H Cornford

    UCL Institute of Neurology, University College London, London, United Kingdom
    For correspondence
    jonathan.cornford.12@ucl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  2. Marion S Mercier

    UCL Institute of Neurology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3929-8118
  3. Marco Leite

    UCL Institute of Neurology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Vincent Magloire

    UCL Institute of Neurology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Michael Häusser

    Wolfson Institute for Biomedical Research, Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Dimitri Michael Kullmann

    UCL Institute of Neurology, University College London, London, United Kingdom
    For correspondence
    d.kullmann@ucl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6696-3545

Funding

Wellcome (095580/Z/11/Z)

  • Jonathan H Cornford
  • Marion S Mercier
  • Marco Leite
  • Vincent Magloire
  • Dimitri Michael Kullmann

Wellcome (212285/Z/18/Z)

  • Dimitri Michael Kullmann

Medical Research Council (MR/L01095X/1)

  • Vincent Magloire

Brain Research Trust

  • Jonathan H Cornford

Wellcome

  • Michael Häusser

Epilepsy Research UK (P1702)

  • Vincent Magloire

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: The study was performed in accordance with the Animals (Scientific Procedures) Act 1986 and reviewed by the Animal Welfare and Ethical Review Body (AWERB) of the UCL Queen Square Institute of Neurology.

Copyright

© 2019, Cornford et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 4,869
    views
  • 794
    downloads
  • 60
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Jonathan H Cornford
  2. Marion S Mercier
  3. Marco Leite
  4. Vincent Magloire
  5. Michael Häusser
  6. Dimitri Michael Kullmann
(2019)
Dendritic NMDA receptors in parvalbumin neurons enable strong and stable neuronal assemblies
eLife 8:e49872.
https://doi.org/10.7554/eLife.49872

Share this article

https://doi.org/10.7554/eLife.49872

Further reading

    1. Neuroscience
    Gergely F Turi, Sasa Teng ... Yueqing Peng
    Research Article

    Synchronous neuronal activity is organized into neuronal oscillations with various frequency and time domains across different brain areas and brain states. For example, hippocampal theta, gamma, and sharp wave oscillations are critical for memory formation and communication between hippocampal subareas and the cortex. In this study, we investigated the neuronal activity of the dentate gyrus (DG) with optical imaging tools during sleep-wake cycles in mice. We found that the activity of major glutamatergic cell populations in the DG is organized into infraslow oscillations (0.01–0.03 Hz) during NREM sleep. Although the DG is considered a sparsely active network during wakefulness, we found that 50% of granule cells and about 25% of mossy cells exhibit increased activity during NREM sleep, compared to that during wakefulness. Further experiments revealed that the infraslow oscillation in the DG was correlated with rhythmic serotonin release during sleep, which oscillates at the same frequency but in an opposite phase. Genetic manipulation of 5-HT receptors revealed that this neuromodulatory regulation is mediated by Htr1a receptors and the knockdown of these receptors leads to memory impairment. Together, our results provide novel mechanistic insights into how the 5-HT system can influence hippocampal activity patterns during sleep.

    1. Neuroscience
    Ulrike Pech, Jasper Janssens ... Patrik Verstreken
    Research Article

    The classical diagnosis of Parkinsonism is based on motor symptoms that are the consequence of nigrostriatal pathway dysfunction and reduced dopaminergic output. However, a decade prior to the emergence of motor issues, patients frequently experience non-motor symptoms, such as a reduced sense of smell (hyposmia). The cellular and molecular bases for these early defects remain enigmatic. To explore this, we developed a new collection of five fruit fly models of familial Parkinsonism and conducted single-cell RNA sequencing on young brains of these models. Interestingly, cholinergic projection neurons are the most vulnerable cells, and genes associated with presynaptic function are the most deregulated. Additional single nucleus sequencing of three specific brain regions of Parkinson’s disease patients confirms these findings. Indeed, the disturbances lead to early synaptic dysfunction, notably affecting cholinergic olfactory projection neurons crucial for olfactory function in flies. Correcting these defects specifically in olfactory cholinergic interneurons in flies or inducing cholinergic signaling in Parkinson mutant human induced dopaminergic neurons in vitro using nicotine, both rescue age-dependent dopaminergic neuron decline. Hence, our research uncovers that one of the earliest indicators of disease in five different models of familial Parkinsonism is synaptic dysfunction in higher-order cholinergic projection neurons and this contributes to the development of hyposmia. Furthermore, the shared pathways of synaptic failure in these cholinergic neurons ultimately contribute to dopaminergic dysfunction later in life.