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 HdhQ7/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.
Highlights
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded CAG repeat in the coding region of the huntingtin gene [1]
In agreement with cGMP levels (Figure 1), neuronal NOS (nNOS) protein levels were unchanged in 8-week-old R6/1 mice compared with wild-type animals (t12=0.064, p=0.95), but there was a dramatic reduction in nNOS levels in the hippocampus of 12, 20- and 30-week-old R6/1 animals compared with agematched controls (12 weeks: t11=6.489, p
In this work we show for the first time that the nNOS/cGMP pathway is severely down-regulated in the hippocampus of R6/1 mice, and that PDE5 inhibition improves memory deficits in these animals
Summary
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded CAG repeat in the coding region of the huntingtin gene [1]. We recently demonstrated that cognitive dysfunction in R6/1 and R6/2 mice, two exon-1 models of HD, correlates with increased hippocampal cAMP-regulated protein kinase (PKA) activity, and that its inhibition re-establishes recognition memory in mutant mice, supporting the idea that PKAdependent processes are occluded in HD mice hippocampus [3]. The nitric oxide/soluble guanylyl cyclase/3',5'-cyclic guanosine monophosphate /cGMP-dependent protein kinase (NO/sGC/cGMP/cGK) signaling pathway has been widely implicated in synaptic plasticity, and in learning and memory in different brain regions, including the hippocampus, cerebellum and amygdala (reviewed in 4). Cognitive loss in Alzheimer’s disease and during aging has been associated with a down-regulation of the NO/cGMP/cGK pathway [9]. The integrity of the NOS/cGMP pathway in the hippocampus of HD mice and patients, and the potential contribution of its alteration to learning and memory defects
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