A role for cerebellum in the hereditary dystonia DYT1

  1. Rachel Fremont
  2. Ambika Tewari
  3. Chantal Angueyra
  4. Kamran Khodakhah  Is a corresponding author
  1. Albert Einstein College of Medicine, United States

Abstract

DYT1 is a debilitating movement disorder caused by loss-of-function mutations in torsinA. How these mutations cause dystonia remains unknown. Mouse models which have embryonically targeted torsinA have failed to recapitulate the dystonia seen in patients, possibly due to differential development compensation between rodents and humans. To address this issue, torsinA was acutely knocked down in select brain regions of adult mice using shRNAs. TorsinA knockdown in the cerebellum, but not in the basal ganglia, was sufficient to induce dystonia. In agreement with a potential developmental compensation for loss of torsinA in rodents, torsinA knockdown in the immature cerebellum failed to produce dystonia. Abnormal motor symptoms in knockdown animals were associated with irregular cerebellar output caused by changes in the intrinsic activity of both Purkinje cells and neurons of the deep cerebellar nuclei. These data identify the cerebellum as the main site of dysfunction in DYT1, and offer new therapeutic targets.

Article and author information

Author details

  1. Rachel Fremont

    Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Ambika Tewari

    Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Chantal Angueyra

    Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Kamran Khodakhah

    Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States
    For correspondence
    k.khodakhah@einstein.yu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7905-5335

Funding

National Institute of Neurological Disorders and Stroke (R01NS079750)

  • Kamran Khodakhah

National Institute of Neurological Disorders and Stroke (ro1NS050808)

  • Kamran Khodakhah

National Institute of Neurological Disorders and Stroke (F30NS071665-)

  • Rachel Fremont

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the Albert Einstein College of Medicine. All surgery was performed under anesthesia, and every effort was made to minimize suffering. Protocol Number: 20160805

Copyright

© 2017, Fremont 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

  • 2,740
    views
  • 658
    downloads
  • 94
    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. Rachel Fremont
  2. Ambika Tewari
  3. Chantal Angueyra
  4. Kamran Khodakhah
(2017)
A role for cerebellum in the hereditary dystonia DYT1
eLife 6:e22775.
https://doi.org/10.7554/eLife.22775

Share this article

https://doi.org/10.7554/eLife.22775

Further reading

    1. Neuroscience
    HaDi MaBouDi, Jasmin Richter ... Lars Chittka
    Research Article

    Active vision, the sensory-motor process through which animals dynamically adjust visual input to sample and prioritise relevant information via photoreceptors, eyes, head, and body movements, is well-documented across species. In small-brained animals like insects, where parallel processing may be limited, active vision for sequential acquisition of visual features might be even more important. We investigated how bumblebees use active vision to distinguish between two visual patterns: a multiplication sign and its 45°-rotated variant, a plus sign. By allowing bees to freely inspect patterns, we analysed their flight paths, inspection times, velocities and regions of focus through high-speed videography. We observed that bees tended to inspect only a small region of each pattern, with a preference for lower and left-side sections, before accurately accepting target or rejecting distractor patterns. The specific pattern areas scanned differed between the plus and multiplication signs, yet flight behaviour remained consistent and specific to each pattern, regardless of whether the pattern was rewarding or punishing. Transfer tests showed that bees could generalise their pattern recognition to partial cues, maintaining scanning strategies and selective attention to learned regions. These findings highlight active vision as a crucial aspect of bumblebees' visual processing, where selective scanning behaviours during flight enhance discrimination accuracy and enable efficient environmental analysis and visual encoding.

    1. Neuroscience
    Zhiping Cao, Wing-Ho Yung, Ya Ke
    Research Article

    Mental and behavioral disorders are associated with extended period of hot weather as found in heatwaves, but the underlying neural circuit mechanism remains poorly known. The posterior paraventricular thalamus (pPVT) is a hub for emotional processing and receives inputs from the hypothalamic preoptic area (POA), the well-recognized thermoregulation center. The present study was designed to explore whether chronic heat exposure leads to aberrant activities in POA recipient pPVT neurons and subsequent changes in emotional states. By devising an air heating paradigm mimicking the condition of heatwaves and utilizing emotion-related behavioral tests, viral tract tracing, in vivo calcium recordings, optogenetic manipulations, and electrophysiological recordings, we found that chronic heat exposure for 3 weeks led to negative emotional valence and hyperarousal states in mice. The pPVT neurons receive monosynaptic excitatory and inhibitory innervations from the POA. These neurons exhibited a persistent increase in neural activity following chronic heat exposure, which was essential for chronic heat-induced emotional changes. Notably, these neurons were also prone to display stronger neuronal activities associated with anxiety responses to stressful situations. Furthermore, we observed saturated neuroplasticity in the POA-pPVT excitatory pathway after chronic heat exposure that occluded further potentiation. Taken together, long-term aberration in the POA to pPVT pathway offers a neurobiological mechanism of emotional and behavioral changes seen in extended periods of hot weather like heatwaves.