A dystonia-like movement disorder with brain and spinal neuronal defects is caused by mutation of the mouse laminin β1 subunit, Lamb1

  1. Yi Bessie Liu
  2. Ambika Tewari
  3. Johnny Salameh
  4. Elena Arystarkhova
  5. Thomas G Hampton
  6. Allison Brashear
  7. Laurie J Ozelius
  8. Kamran Khodakhah
  9. Kathleen J Sweadner  Is a corresponding author
  1. Harvard Medical School, United States
  2. Albert Einstein College of Medicine, United States
  3. University of Massachusetts Medical School, United States
  4. Mouse Specifics Inc., United States
  5. Wake Forest University School of Medicine, United States

Abstract

A new mutant mouse (lamb1t) exhibits intermittent dystonic hindlimb movements and postures when awake, and hyperextension when asleep. Experiments showed co-contraction of opposing muscle groups, and indicated that symptoms depended on the interaction of brain and spinal cord. SNP mapping and exome sequencing identified the dominant causative mutation in the Lamb1 gene. Laminins are extracellular matrix proteins, widely expressed but also known to be important in synapse structure and plasticity. In accordance, awake recording in the cerebellum detected abnormal output from a circuit of two Lamb1-expressing neurons, Purkinje cells and their deep cerebellar nucleus targets, during abnormal postures. We propose that dystonia-like symptoms result from lapses in descending inhibition, exposing excess activity in intrinsic spinal circuits that coordinate muscles. The mouse is a new model for testing how dysfunction in the CNS causes specific abnormal movements and postures.

Article and author information

Author details

  1. Yi Bessie Liu

    Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  2. Ambika Tewari

    Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States
    Competing interests
    No competing interests declared.
  3. Johnny Salameh

    Department of Neurology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    No competing interests declared.
  4. Elena Arystarkhova

    Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  5. Thomas G Hampton

    Neuroscience Discovery Core, Mouse Specifics Inc., Framingham, United States
    Competing interests
    Thomas G Hampton, owner of the company that has commercialized the gait analysis instrumentation described.
  6. Allison Brashear

    Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, United States
    Competing interests
    Allison Brashear, performs research at Wake Forest with grants from Allergan, Ipsen, and Merz, and has consulting relationships with Allergan and Concerta. Her conflict of interest is managed by Wake Forest School of Medicine.
  7. Laurie J Ozelius

    Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  8. Kamran Khodakhah

    Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States
    Competing interests
    No competing interests declared.
  9. Kathleen J Sweadner

    Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States
    For correspondence
    sweadner@helix.mgh.harvard.edu
    Competing interests
    No competing interests declared.

Ethics

Animal experimentation: All animal research followed the NRC Guide for the Care and Use of Laboratory Animals and the policies of the Massachusetts General Hospital or Albert Einstein College of Medicine: MGH IACUC approved protocol 2011N000108, and Albert Einstein approved protocol 20130801.

Copyright

© 2015, Liu 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

  • 3,875
    views
  • 402
    downloads
  • 21
    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. Yi Bessie Liu
  2. Ambika Tewari
  3. Johnny Salameh
  4. Elena Arystarkhova
  5. Thomas G Hampton
  6. Allison Brashear
  7. Laurie J Ozelius
  8. Kamran Khodakhah
  9. Kathleen J Sweadner
(2015)
A dystonia-like movement disorder with brain and spinal neuronal defects is caused by mutation of the mouse laminin β1 subunit, Lamb1
eLife 4:e11102.
https://doi.org/10.7554/eLife.11102

Share this article

https://doi.org/10.7554/eLife.11102

Further reading

    1. Neuroscience
    Marco Paoli, Antoine Wystrach ... Martin Giurfa
    Research Article

    Odour processing exhibits multiple parallels between vertebrate and invertebrate olfactory systems. Insects, in particular, have emerged as relevant models for olfactory studies because of the tractability of their olfactory circuits. Here, we used fast calcium imaging to track the activity of projection neurons in the honey bee antennal lobe (AL) during olfactory stimulation at high temporal resolution. We observed a heterogeneity of response profiles and an abundance of inhibitory activities, resulting in various response latencies and stimulus-specific post-odour neural signatures. Recorded calcium signals were fed to a mushroom body (MB) model constructed implementing the fundamental features of connectivity between olfactory projection neurons, Kenyon cells (KC), and MB output neurons (MBON). The model accounts for the increase of odorant discrimination in the MB compared to the AL and reveals the recruitment of two distinct KC populations that represent odorants and their aftersmell as two separate but temporally coherent neural objects. Finally, we showed that the learning-induced modulation of KC-to-MBON synapses can explain both the variations in associative learning scores across different conditioning protocols used in bees and the bees' response latency. Thus, it provides a simple explanation of how the time contingency between the stimulus and the reward can be encoded without the need for time tracking. This study broadens our understanding of olfactory coding and learning in honey bees. It demonstrates that a model based on simple MB connectivity rules and fed with real physiological data can explain fundamental aspects of odour processing and associative learning.

    1. Neuroscience
    Yihe Weng, Johann Kruschwitz ... IMAGEN Consortium
    Research Article

    Substance use, including cigarettes and cannabis, is associated with poorer sustained attention in late adolescence and early adulthood. Previous studies were predominantly cross-sectional or under-powered and could not indicate if impairment in sustained attention was a predictor of substance use or a marker of the inclination to engage in such behavior. This study explored the relationship between sustained attention and substance use across a longitudinal span from ages 14 to 23 in over 1000 participants. Behaviors and brain connectivity associated with diminished sustained attention at age 14 predicted subsequent increases in cannabis and cigarette smoking, establishing sustained attention as a robust biomarker for vulnerability to substance use. Individual differences in network strength relevant to sustained attention were preserved across developmental stages and sustained attention networks generalized to participants in an external dataset. In summary, brain networks of sustained attention are robust, consistent, and able to predict aspects of later substance use.