Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 12, Pages 4906-4911Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0811228106
Keywords
actin polymerization; CAG140; long-term potentiation; theta burst stimulation; unsupervised learning
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Funding
- Cortex Pharmaceuticals, Inc.
- National Institute of Neurological Disorders and Stroke [NS051823, NS045260]
- Huntington's Disease Drug Works Foundation
- National Institutes on Aging [AG00096]
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Cognitive problems occur in asymptomatic gene carriers of Huntington's disease (HD), and mouse models of the disease exhibit impaired learning and substantial deficits in the cytoskeletal changes that stabilize long-term potentiation (LTP). The latter effects may be related to the decreased production of brain-derived neurotrophic factor (BDNF) associated with the HD mutation. This study asked whether up-regulating endogenous BDNF levels with an ampakine, a positive modulator of AMPA-type glutamate receptors, rescues plasticity and reduces learning problems in HD (CAG140) mice. Twice-daily injections of a short half-life ampakine normalized BDNF levels, activity-driven actin polymerization in dendritic spines, and LTP stabilization in 8-week-old mutants. Comparable results were obtained in 16-week-old HD mice with more severe LTP deficits. Ampakine treatments had no measurable effect on the decreased locomotor activity observed in the mutants but offset their impairments in long-term memory. Given that ampakines are well tolerated in clinical trials and were effective in this study after brief exposures, these results suggest a novel strategy for chronic treatment of the cognitive difficulties that occur in the early stages of HD.
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