Early dysfunction and progressive degeneration of the subthalamic nucleus in mouse models of Huntington's disease
- Feinberg School of Medicine, Northwestern University, United States
Abstract
The subthalamic nucleus (STN) is an element of cortico-basal ganglia-thalamo-cortical circuitry critical for action suppression. In Huntington's disease (HD) action suppression is impaired, resembling the effects of STN lesioning or inactivation. To explore this potential linkage, the STN was studied in BAC transgenic and Q175 knock-in mouse models of HD. At < 2 and 6 months of age autonomous STN activity was impaired due to activation of KATP channels. STN neurons exhibited prolonged NMDA receptor-mediated synaptic currents, caused by a deficit in glutamate uptake, and elevated mitochondrial oxidant stress, which was ameliorated by NMDA receptor antagonism. STN activity was rescued by NMDA receptor antagonism or breakdown of hydrogen peroxide. At 12 months of age approximately 30% of STN neurons were lost, as in HD. Together these data argue that dysfunction within the STN is an early feature of HD that may contribute to its expression and course.
Article and author information
Author details
Funding
CHDI Foundation
- Jeremy F Atherton
- Mark D Bevan
National Institutes of Health (2R37 NS041280 and 2P50 NS047085)
- Eileen L McIver
- David L Wokosin
- D James Surmeier
- Mark D Bevan
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 accordance with the policies of the Society for Neuroscience and the National Institutes of Health. All animals were handled according to approved Institutional Animal Care and Use Committee protocols (IS00001185) of Northwestern University. All procedures were performed under isoflurane or ketamine/xylazine anesthesia, and every effort was made to minimize suffering.
Copyright
© 2016, Atherton 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.
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Early dysfunction and progressive degeneration of the subthalamic nucleus in mouse models of Huntington's disease
eLife 5:e21616.
https://doi.org/10.7554/eLife.21616
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