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

  • 748
    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
    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.

    1. Neuroscience
    Sven Ohl, Martin Rolfs
    Research Article

    Detecting causal relations structures our perception of events in the world. Here, we determined for visual interactions whether generalized (i.e. feature-invariant) or specialized (i.e. feature-selective) visual routines underlie the perception of causality. To this end, we applied a visual adaptation protocol to assess the adaptability of specific features in classical launching events of simple geometric shapes. We asked observers to report whether they observed a launch or a pass in ambiguous test events (i.e. the overlap between two discs varied from trial to trial). After prolonged exposure to causal launch events (the adaptor) defined by a particular set of features (i.e. a particular motion direction, motion speed, or feature conjunction), observers were less likely to see causal launches in subsequent ambiguous test events than before adaptation. Crucially, adaptation was contingent on the causal impression in launches as demonstrated by a lack of adaptation in non-causal control events. We assessed whether this negative aftereffect transfers to test events with a new set of feature values that were not presented during adaptation. Processing in specialized (as opposed to generalized) visual routines predicts that the transfer of visual adaptation depends on the feature similarity of the adaptor and the test event. We show that the negative aftereffects do not transfer to unadapted launch directions but do transfer to launch events of different speeds. Finally, we used colored discs to assign distinct feature-based identities to the launching and the launched stimulus. We found that the adaptation transferred across colors if the test event had the same motion direction as the adaptor. In summary, visual adaptation allowed us to carve out a visual feature space underlying the perception of causality and revealed specialized visual routines that are tuned to a launch’s motion direction.