Neuronal glutamate transporters control reciprocal inhibition and gain modulation in D1 medium spiny neurons

Abstract

Understanding the function of glutamate transporters has broad implications for explaining how neurons integrate information and relay it through complex neuronal circuits. Most of what is currently known about glutamate transporters, specifically their ability to maintain glutamate homeostasis and limit glutamate diffusion away from the synaptic cleft, is based on studies of glial glutamate transporters. By contrast, little is known about the functional implications of neuronal glutamate transporters. The neuronal glutamate transporter EAAC1 is widely expressed throughout the brain, particularly in the striatum, the primary input nucleus of the basal ganglia, a region implicated with movement execution and reward. Here, we show that EAAC1 limits synaptic excitation onto a population of striatal medium spiny neurons identified for their expression of D1 dopamine receptors (D1-MSNs). In these cells, EAAC1 also contributes to strengthen lateral inhibition from other D1-MSNs. Together, these effects contribute to reduce the gain of the input-output relationship and increase the offset at increasing levels of synaptic inhibition in D1-MSNs. By reducing the sensitivity and dynamic range of action potential firing in D1-MSNs, EAAC1 limits the propensity of mice to rapidly switch between behaviors associated with different reward probabilities. Together, these findings shed light on some important molecular and cellular mechanisms implicated with behavior flexibility in mice.

Data availability

All primary data used in this work and complete statistical analyses for each figure have been deposited to the Open Science Framework (https://osf.io/dw5n7/).

The following data sets were generated

Article and author information

Author details

  1. Maurice A Petroccione

    Department of Biology, University at Albany, State University of New York, Albany, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Lianna Y D'Brant

    Department of Biology, University at Albany, State University of New York, Albany, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Nurat Affinnih

    Department of Biology, University at Albany, State University of New York, Albany, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4203-6410
  4. Patrick H Wehrle

    Department of Biology, University at Albany, State University of New York, Albany, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Gabrielle C Todd

    Department of Biology, University at Albany, State University of New York, Albany, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Shergil Zahid

    Department of Biology, University at Albany, State University of New York, Albany, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Haley E Chesbro

    Department of Biology, University at Albany, State University of New York, Albany, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Ian L Tschang

    Department of Biology, University at Albany, State University of New York, Albany, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Annalisa Scimemi

    Department of Biology, University at Albany, State University of New York, Albany, United States
    For correspondence
    scimemia@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4975-093X

Funding

National Science Foundation (IOS1655365)

  • Annalisa Scimemi

National Science Foundation (IOS2011998)

  • Annalisa Scimemi

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

Ethics

Animal experimentation: All experimental procedures were performed in accordance with protocols approved by the Institutional Animal Care and Use Committee at the State University of New York (SUNY) Albany and guidelines described in the National Institutes of Health's Guide for the Care and Use of Laboratory Animals.

Copyright

© 2023, Petroccione 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

  • 743
    views
  • 140
    downloads
  • 3
    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. Maurice A Petroccione
  2. Lianna Y D'Brant
  3. Nurat Affinnih
  4. Patrick H Wehrle
  5. Gabrielle C Todd
  6. Shergil Zahid
  7. Haley E Chesbro
  8. Ian L Tschang
  9. Annalisa Scimemi
(2023)
Neuronal glutamate transporters control reciprocal inhibition and gain modulation in D1 medium spiny neurons
eLife 12:e81830.
https://doi.org/10.7554/eLife.81830

Share this article

https://doi.org/10.7554/eLife.81830

Further reading

    1. Neuroscience
    Brian C Ruyle, Sarah Masud ... Jose A Morón
    Research Article

    Millions of Americans suffering from Opioid Use Disorders face a high risk of fatal overdose due to opioid-induced respiratory depression (OIRD). Fentanyl, a powerful synthetic opioid, is a major contributor to the rising rates of overdose deaths. Reversing fentanyl overdoses has proved challenging due to its high potency and the rapid onset of OIRD. We assessed the contributions of central and peripheral mu opioid receptors (MORs) in mediating fentanyl-induced physiological responses. The peripherally restricted MOR antagonist naloxone methiodide (NLXM) both prevented and reversed OIRD to a degree comparable to that of naloxone (NLX), indicating substantial involvement of peripheral MORs to OIRD. Interestingly, NLXM-mediated OIRD reversal did not produce aversive behaviors observed after NLX. We show that neurons in the nucleus of the solitary tract (nTS), the first central synapse of peripheral afferents, exhibit a biphasic activity profile following fentanyl exposure. NLXM pretreatment attenuates this activity, suggesting that these responses are mediated by peripheral MORs. Together, these findings establish a critical role for peripheral MORs, including ascending inputs to the nTS, as sites of dysfunction during OIRD. Furthermore, selective peripheral MOR antagonism could be a promising therapeutic strategy for managing OIRD by sparing CNS-driven acute opioid-associated withdrawal and aversion observed after NLX.

    1. Neuroscience
    David C Williams, Amanda Chu ... Michael A McDannald
    Research Advance Updated

    Recognizing and responding to threat cues is essential to survival. Freezing is a predominant threat behavior in rats. We have recently shown that a threat cue can organize diverse behaviors beyond freezing, including locomotion (Chu et al., 2024). However, that experimental design was complex, required many sessions, and had rats receive many foot shock presentations. Moreover, the findings were descriptive. Here, we gave female and male Long Evans rats cue light illumination paired or unpaired with foot shock (eight total) in a conditioned suppression setting using a range of shock intensities (0.15, 0.25, 0.35, or 0.50 mA). We found that conditioned suppression was only observed at higher foot shock intensities (0.35 mA and 0.50 mA). We constructed comprehensive temporal ethograms by scoring 22,272 frames across 12 behavior categories in 200-ms intervals around cue light illumination. The 0.50 mA and 0.35 mA shock-paired visual cues suppressed reward seeking, rearing, and scaling, as well as light-directed rearing and light-directed scaling. These shock-paired visual cues further elicited locomotion and freezing. Linear discriminant analyses showed that ethogram data could accurately classify rats into paired and unpaired groups. Using complete ethogram data produced superior classification compared to behavior subsets, including an immobility subset featuring freezing. The results demonstrate diverse threat behaviors – in a short and simple procedure – containing sufficient information to distinguish the visual fear conditioning status of individual rats.