A tonic nicotinic brake controls spike timing in striatal spiny projection neurons

  1. Lior Matityahu
  2. Jeffrey M Malgady
  3. Meital Schirelman
  4. Yvonne Johansson
  5. Jennifer Wilking
  6. Gilad Silberberg
  7. Joshua A Goldberg  Is a corresponding author
  8. Joshua L Plotkin  Is a corresponding author
  1. The Hebrew University of Jerusalem, Israel
  2. Stony Brook University, United States
  3. University College London, United Kingdom
  4. Karolinska Institutet, Sweden

Abstract

Striatal spiny projection neurons (SPNs) transform convergent excitatory corticostriatal inputs into an inhibitory signal that shapes basal ganglia output. This process is fine-tuned by striatal GABAergic interneurons (GINs), which receive overlapping cortical inputs and mediate rapid corticostriatal feedforward inhibition of SPNs. Adding another level of control, cholinergic interneurons (CINs), which are also vigorously activated by corticostriatal excitation, can disynaptically inhibit SPNs by activating α4β2 nicotinic acetylcholine receptors (nAChRs) on various GINs. Measurements of this disynaptic inhibitory pathway, however, indicate that it is too slow to compete with direct GIN-mediated feed-forward inhibition. Moreover, functional nAChRs are also present on populations of GINs that respond only weakly to phasic activation of CINs, such as parvalbumin-positive fast-spiking interneurons (PV-FSIs), making the overall role of nAChRs in shaping striatal synaptic integration unclear. Using acute striatal slices from mice we show that upon synchronous optogenetic activation of corticostriatal projections blockade of α4β2 nAChRs shortened SPN spike latencies and increased postsynaptic depolarizations. The nAChR-dependent inhibition was mediated by downstream GABA release, and data suggest that the GABA source was not limited to GINs that respond strongly to phasic CIN activation. In particular, the observed decrease in spike latency caused by nAChR blockade was associated with a diminished frequency of spontaneous inhibitory postsynaptic currents in SPNs, a parallel hyperpolarization of PV-FSIs, and was occluded by pharmacologically preventing cortical activation of PV-FSIs. Taken together, we describe a role for tonic (as opposed to phasic) activation of nAChRs in striatal function. We conclude that tonic activation of nAChRs by CINs maintains a GABAergic brake on cortically-driven striatal output by 'priming' feedforward inhibition, a process that may shape SPN spike timing, striatal processing and synaptic plasticity.

Data availability

All analyzed data sets, whether included in figures or referenced as 'not shown', have been uploaded to OSF and made publically available: https://osf.io/7kazd

Article and author information

Author details

  1. Lior Matityahu

    Department of Medical Neurobiology, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  2. Jeffrey M Malgady

    Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1129-2155
  3. Meital Schirelman

    Department of Medical Neurobiology, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  4. Yvonne Johansson

    Sainsbury Wellcome Centre for Neural Circuits and Behaviour, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Jennifer Wilking

    Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Gilad Silberberg

    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9964-505X
  7. Joshua A Goldberg

    Department of Medical Neurobiology, The Hebrew University of Jerusalem, Jerusalem, Israel
    For correspondence
    joshua.goldberg2@mail.huji.ac.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5740-4087
  8. Joshua L Plotkin

    Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, United States
    For correspondence
    joshua.plotkin@stonybrook.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6232-7613

Funding

BSF (2017020)

  • Joshua A Goldberg
  • Joshua L Plotkin

ISF (154/14)

  • Joshua A Goldberg

ERC Consolidator (646880)

  • Joshua A Goldberg

NIH (R01 NS104089/NINDS)

  • Joshua L Plotkin

NIH (NS022061/NINDS)

  • Joshua L Plotkin

Swedish Brain Fund grant (FO2021-0333)

  • Gilad Silberberg

Swedish Brain Fund grant (PS2020-0020)

  • Yvonne Johansson

Swedish Research Council grant (2019-01254)

  • Gilad Silberberg

Wallenberg Academy Fellowship (KAW 2017.0273)

  • Gilad Silberberg

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

Reviewing Editor

  1. Jun Ding, Stanford University, United States

Ethics

Animal experimentation: All experimental procedures on mice adhered to and received prior written approval from the Institutional Animal Care and Use Committees of the Hebrew University of Jerusalem (MD-14-14195-3 and MD-18-15657-3) and of Stony Brook University (737496) and of the local ethics committee of Stockholm, Stockholms Norra djurförsöksetiska nämnd (N2022_2020).

Version history

  1. Preprint posted: November 3, 2021 (view preprint)
  2. Received: November 24, 2021
  3. Accepted: May 15, 2022
  4. Accepted Manuscript published: May 17, 2022 (version 1)
  5. Version of Record published: May 27, 2022 (version 2)

Copyright

© 2022, Matityahu 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.

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  1. Lior Matityahu
  2. Jeffrey M Malgady
  3. Meital Schirelman
  4. Yvonne Johansson
  5. Jennifer Wilking
  6. Gilad Silberberg
  7. Joshua A Goldberg
  8. Joshua L Plotkin
(2022)
A tonic nicotinic brake controls spike timing in striatal spiny projection neurons
eLife 11:e75829.
https://doi.org/10.7554/eLife.75829

Share this article

https://doi.org/10.7554/eLife.75829

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