Abstract
Huntington's disease (HD) patients and mouse models show learning and memory impairment associated with hippocampal dysfunction. The neuronal nitric oxide synthase/3',5'-cyclic guanosine monophosphate (nNOS/cGMP) pathway is implicated in synaptic plasticity, and in learning and memory processes. Here, we examined the nNOS/cGMP pathway in the hippocampus of HD mice to determine whether it can be a good therapeutic target for cognitive improvement in HD. We analyzed hippocampal nNOS and phosphodiesterase (PDE) 5 and 9 levels in R6/1 mice, and cGMP levels in the hippocampus of R6/1, R6/2 and Hdh(Q7/Q111) mice, and of HD patients. We also investigated whether sildenafil, a PDE5 inhibitor, could improve cognitive deficits in R6/1 mice. We found that hippocampal cGMP levels were 3-fold lower in 12-week-old R6/1 mice, when they show deficits in object recognition memory and in passive avoidance learning. Consistent with hippocampal cGMP levels, nNOS levels were down-regulated, while there were no changes in the levels of PDE5 and PDE9 in R6/1 mice. A single intraperitoneal injection of sildenafil (3 mg/Kg) immediately after training increased cGMP levels, and improved memory in R6/1 mice, as assessed by using the novel object recognition and the passive avoidance test. Importantly, cGMP levels were also reduced in R6/2 mouse and human HD hippocampus. Therefore, the regulation of hippocampal cGMP levels can be a suitable treatment for cognitive impairment in HD.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Animals
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Anxiety / genetics
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Anxiety / physiopathology
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Anxiety / prevention & control
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Autopsy
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Avoidance Learning / drug effects
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Avoidance Learning / physiology
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Blotting, Western
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Cognition Disorders / genetics
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Cognition Disorders / physiopathology*
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Cognition Disorders / prevention & control
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Cyclic GMP / metabolism*
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Down-Regulation / drug effects
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Female
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Hippocampus / drug effects
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Hippocampus / metabolism*
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Humans
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Huntington Disease / genetics
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Huntington Disease / physiopathology*
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Huntington Disease / prevention & control
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Male
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Memory / drug effects
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Memory / physiology*
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Mice
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Mice, Transgenic
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Middle Aged
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Motor Activity / drug effects
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Motor Activity / genetics
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Motor Activity / physiology
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Nitric Oxide Synthase Type I / metabolism
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Phosphodiesterase 5 Inhibitors / pharmacology
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Piperazines / pharmacology
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Purines / pharmacology
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Sildenafil Citrate
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Sulfones / pharmacology
Substances
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Phosphodiesterase 5 Inhibitors
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Piperazines
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Purines
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Sulfones
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Sildenafil Citrate
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Nitric Oxide Synthase Type I
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Cyclic GMP
Grants and funding
This work was supported by Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain (PI10/01072 to EP-N), Redes Temáticas de Investigación Cooperativa Sanitaria (grant number RD06/0010/0006), Ministerio de Economia y Competitividad, Spain (SAF2011-29507 to JA), and Generalitat de Catalunya, Spain (2009SGR-00326 to JA). AS and AG and are supported by Ministerio de Economia y Competitividad, Spain (Juan de la Cierva subprograme, JCI-2010-08207 and CAPLE2009-0089, respectively). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.