Aberrant heart rate and brainstem brain-derived neurotrophic factor (BDNF) signaling in a mouse model of Huntington's disease

Griffioen, Kathleen J.; Wan, Ruiqian; Brown, Tashalee R.; Okun, Eitan; Camandola, Simonetta; Mughal, Mohamed R.; Phillips, Terry M.; Mattson, Mark P.

doi:10.1016/j.neurobiolaging.2011.11.030

« Previous Next »Neurobiology of Aging
Volume 33, Issue 7 , Pages 1481.e1-1481.e5, July 2012

Aberrant heart rate and brainstem brain-derived neurotrophic factor (BDNF) signaling in a mouse model of Huntington's disease

Kathleen J. Griffioen
- Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA
Ruiqian Wan
- Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA
Tashalee R. Brown
- Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA
- Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, NY, New York, USA
Eitan Okun
- The Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan, 52900, Israel
Simonetta Camandola
- Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA
Mohamed R. Mughal
- Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA
Terry M. Phillips
- Laboratory of Bioengineering & Physical Science, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD
Mark P. Mattson
- Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA
- Corresponding author. Tel: +1-410 558 8643; fax: +1 (410)558 8323

Received 23 June 2011; received in revised form 28 November 2011; accepted 28 November 2011. published online 04 January 2012.

Abstract

Huntington's disease (HD) is associated with profound autonomic dysfunction including dysregulation of cardiovascular control often preceding cognitive or motor symptoms. Brain-derived neurotrophic factor (BDNF) levels are decreased in the brains of HD patients and HD mouse models, and restoring BDNF levels prevents neuronal loss and extends survival in HD mice. We reasoned that heart rate changes in HD may be associated with altered BDNF signaling in cardiovascular control nuclei in the brainstem. Here we show that heart rate is elevated in HD (N171-82Q) mice at presymptomatic and early disease stages, and heart rate responses to restraint stress are attenuated. BDNF levels were significantly reduced in brainstem regions containing cardiovascular nuclei in HD mice and human HD patients. Central administration of BDNF restored the heart rate to control levels. Our findings establish a link between diminished BDNF expression in brainstem cardiovascular nuclei and abnormal heart rates in HD mice, and suggest a novel therapeutic target for correcting cardiovascular dysfunction in HD.

Keywords: Huntington's disease , Brainstem , BDNF