Aged neuronal nitric oxide knockout mice show preserved olfactory learning in both social recognition and odor-conditioning tasks

Abstract

There is evidence for both neurotoxic and neuroprotective roles of nitric oxide (NO) in the brain and changes in the expression of the neuronal isoform of NO synthase (nNOS) gene occur during aging. The current studies have investigated potential support for either a neurotoxic or neuroprotective role of NO derived from nNOS in the context of aging by comparing olfactory learning and locomotor function in young compared to old nNOS knockout (nNOS−/−) and wildtype control mice. Tasks involving social recognition and olfactory conditioning paradigms showed that old nNOS−/− animals had improved retention of learning compared to similar aged wildtype controls. Young nNOS−/− animals showed superior reversal learning to wildtypes in a conditioned learning task, although their performance was weakened with age. Interestingly, whereas young nNOS−/− animals were impaired in long term memory for social odors compared to wildtype controls, in old animals this pattern was reversed, possibly indicating beneficial compensatory changes influencing olfactory memory may occur during aging in nNOS−/− animals. Possibly such compensatory changes may have involved increased NO from other NOS isoforms since the memory deficit in young nNOS−/− animals could be rescued by the NO-donor, molsidomine. Both nNOS−/− and wildtype animals showed an age-associated decline in locomotor activity although young nNOS−/− animals were significantly more active than wildtypes, possibly due to an increased interest in novelty. Overall our findings suggest that lack of NO release via nNOS may protect animals to some extent against age-associated cognitive decline in memory tasks typically involving olfactory and hippocampal regions, but not against declines in reversal learning or locomotor activity.

Effects of environmental enrichment in aged mice on anxiety-like behaviors and neuronal nitric oxide synthase expression in the brain

“…Pharmacological systemic inhibition of nNOS is known to have positive effects on anxiety-like behaviors [6]. In addition, a recent study has reported that lack of NO release via nNOS may protect animals to some extent against age-associated neurodegenerative changes [13]. Thus, this result suggests that NO derived from nNOS by aging acts as a neurotoxin rather than a neuroprotectant.…”

“…These findings also suggest possible regional differences in nNOS expression in the aged brain. In this regard, a previous study reported that nNOSÀ/À mice were protected from age-associated decline in olfactory learning tasks [13]. However the role of nNOS on anxiety in aged mice is not well known.…”

The Molecular Simulation Study of nNOS Activation Induced by the Interaction Between Its Calmodulin-Binding Domain and SUMO1

“…This theoretical study of nNOS SUMO-ylation provides a new pathological outlook to nNOS inhibition in cognitive decline and myopathies (Kelley et al, 2009(Kelley et al, , 2011Ito et al, 2013;Pavesi et al, 2013;Baldelli et al, 2014;James et al, 2015). Generally, the hyperactivity of nNOS produces excessive nitrogen oxide, which is toxic to neurons after acute brain injury (Yu et al, 2008;Zhou et al, 2010;Yin et al, 2013;Favié et al, 2018;Qu et al, 2020).…”

“…Neuronal nitric oxide synthase (nNOS), an enzyme constitutively expressed and of high levels in the mammalian brain and skeletal muscle, catalyzes the conversion of L-arginine to nitric oxide. Previous studies have suggested that nNOS is required for learning and long-term memory (Kelley et al, 2009(Kelley et al, , 2011Pavesi et al, 2013;James et al, 2015), as well as skeletal muscle contraction (Ito et al, 2013;Baldelli et al, 2014). However, excessive activation of nNOS in the neurons results in oxidative and nitrosative stress, which is associated with neuronal loss in various neuropsychiatric disorders including hypoxic-ischemic encephalopathy (Yu et al, 2008;Yin et al, 2013;Favié et al, 2018), ischemic stroke (Zhou et al, 2010), and traumatic brain injury (Qu et al, 2020).…”

The eNOS isoform exhibits increased expression and activation in the main olfactory bulb of nNOS knock-out mice

“…As no significant differences were detected between experimental groups, it seems that the absence of nNOS directly affects olfaction in mice. Other published work ( James et al, 2015 ) describes that nNOS-KO mice show better olfactory learning and increased locomotor ability compared to wild-type animals. Apparently, these results seem to contradict ours, both for the buried food test and in the movement analyses.…”