Roundabout receptor 2 maintains inhibitory control of the adult midbrain

  1. Bryan B Gore
  2. Samara M Miller
  3. Yong Sang Jo
  4. Madison Baird
  5. Mrinalini Hoon
  6. Christina A Sanford
  7. Avery Hunker
  8. Weining Lu
  9. Rachel O Wong
  10. Larry S Zweifel  Is a corresponding author
  1. University of Washington, United Kingdom
  2. University of Washington, United States
  3. Boston University Medical Center, United States

Abstract

The maintenance of excitatory and inhibitory balance in the brain is essential for its function. Here we find that the developmental axon guidance receptor Roundabout 2 (Robo2) is critical for the maintenance of inhibitory synapses in the adult ventral tegmental area (VTA), a brain region important for the production of the neurotransmitter dopamine. Following selective genetic inactivation of Robo2 in the adult VTA of mice, reduced inhibitory control results in altered neural activity patterns, enhanced phasic dopamine release, behavioral hyperactivity, associative learning deficits, and a paradoxical inversion of psychostimulant responses. These behavioral phenotypes could be phenocopied by selective inactivation of synaptic transmission from local GABAergic neurons of the VTA, demonstrating an important function for Robo2 in regulating the excitatory and inhibitory balance of the adult brain.

Article and author information

Author details

  1. Bryan B Gore

    Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Samara M Miller

    Department of Pharmacology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yong Sang Jo

    Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Madison Baird

    Department of Pharmacology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Mrinalini Hoon

    Department of Biological Structure, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Christina A Sanford

    Department of Pharmacology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Avery Hunker

    Department of Pharmacology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Weining Lu

    Department of Medicine, Boston University Medical Center, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Rachel O Wong

    Department of Biological Structure, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Larry S Zweifel

    Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, United States
    For correspondence
    larryz@uw.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3465-5331

Funding

National Institutes of Health (R01-MH094536)

  • Larry S Zweifel

National Institute for Health Research (EY10699)

  • Rachel O Wong

National Institute for Health Research (R01-DK078226)

  • Weining Lu

National Institutes of Health (R01-MH104450)

  • Larry S Zweifel

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 experiments were done in accordance with a protocol (4249-01) approved by the University of Washington Animal Care and Use Committee.

Copyright

© 2017, Gore 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

  • 1,274
    views
  • 251
    downloads
  • 15
    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. Bryan B Gore
  2. Samara M Miller
  3. Yong Sang Jo
  4. Madison Baird
  5. Mrinalini Hoon
  6. Christina A Sanford
  7. Avery Hunker
  8. Weining Lu
  9. Rachel O Wong
  10. Larry S Zweifel
(2017)
Roundabout receptor 2 maintains inhibitory control of the adult midbrain
eLife 6:e23858.
https://doi.org/10.7554/eLife.23858

Share this article

https://doi.org/10.7554/eLife.23858

Further reading

    1. Neuroscience
    Hannah Bos, Christoph Miehl ... Brent Doiron
    Research Article

    Synaptic inhibition is the mechanistic backbone of a suite of cortical functions, not the least of which are maintaining network stability and modulating neuronal gain. In cortical models with a single inhibitory neuron class, network stabilization and gain control work in opposition to one another – meaning high gain coincides with low stability and vice versa. It is now clear that cortical inhibition is diverse, with molecularly distinguished cell classes having distinct positions within the cortical circuit. We analyze circuit models with pyramidal neurons (E) as well as parvalbumin (PV) and somatostatin (SOM) expressing interneurons. We show how, in E – PV – SOM recurrently connected networks, SOM-mediated modulation can lead to simultaneous increases in neuronal gain and network stability. Our work exposes how the impact of a modulation mediated by SOM neurons depends critically on circuit connectivity and the network state.

    1. Genetics and Genomics
    2. Neuroscience
    Martina Rudgalvyte, Zehan Hu ... Dominique A Glauser
    Research Article

    Thermal nociception in Caenorhabditis elegans is regulated by the Ca²+/calmodulin-dependent protein kinase CMK-1, but its downstream effectors have remained unclear. Here, we combined in vitro kinase assays with mass-spectrometry-based phosphoproteomics to identify hundreds of CMK-1 substrates, including the calcineurin A subunit TAX-6, phosphorylated within its conserved regulatory domain. Genetic and pharmacological analyses reveal multiple antagonistic interactions between CMK-1 and calcineurin signaling in modulating both naive thermal responsiveness and adaptation to repeated noxious stimuli. Cell-specific manipulations indicate that CMK-1 acts in AFD and ASER thermo-sensory neurons, while TAX-6 functions in FLP thermo-sensory neurons and downstream interneurons. Since CMK-1 and TAX-6 act in distinct cell types, the phosphorylation observed in vitro might not directly underlie the behavioral phenotype. Instead, the opposing effects seem to arise from their distributed roles within the sensory circuit. Overall, our study provides (1) a resource of candidate CMK-1 targets for further dissecting CaM kinase signaling and (2) evidence of a previously unrecognized, circuit-level antagonism between CMK-1 and calcineurin pathways. These findings highlight a complex interplay of signaling modules that modulate thermal nociception and adaptation, offering new insights into potentially conserved mechanisms that shape nociceptive plasticity and pain (de)sensitization in more complex nervous systems.