Hippocampal expression of myelin-associated inhibitors is induced with age-related cognitive decline and correlates with deficits of spatial learning and memory

Department of Pharmacology, R130, Hershey Center for Applied Research, Penn State College of Medicine, Hershey, PA 17033, USA.
Journal of Neurochemistry (Impact Factor: 4.28). 01/2012; 121(1):77-98. DOI: 10.1111/j.1471-4159.2012.07671.x
Source: PubMed


J. Neurochem. (2012) 121, 77–98.
Impairment of cognitive functions including hippocampus-dependent spatial learning and memory affects nearly half of the aged population. Age-related cognitive decline is associated with synaptic dysfunction that occurs in the absence of neuronal cell loss, suggesting that impaired neuronal signaling and plasticity may underlie age-related deficits of cognitive function. Expression of myelin-associated inhibitors (MAIs) of synaptic plasticity, including the ligands myelin-associated glycoprotein, neurite outgrowth inhibitor A, and oligodendrocyte myelin glycoprotein, and their common receptor, Nogo-66 receptor, was examined in hippocampal synaptosomes and Cornu ammonis area (CA)1, CA3 and dentate gyrus subregions derived from adult (12–13 months) and aged (26–28 months) Fischer 344 × Brown Norway rats. Rats were behaviorally phenotyped by Morris water maze testing and classified as aged cognitively intact (n = 7–8) or aged cognitively impaired (n = 7–10) relative to adults (n = 5–7). MAI protein expression was induced in cognitively impaired, but not cognitively intact, aged rats and correlated with cognitive performance in individual rats. Immunohistochemical experiments demonstrated that up-regulation of MAIs occurs, in part, in hippocampal neuronal axons and somata. While a number of pathways and processes are altered with brain aging, we report a coordinated induction of myelin-associated inhibitors of functional and structural plasticity only in cognitively impaired aged rats. Induction of MAIs may decrease stimulus-induced synaptic strengthening and structural remodeling, ultimately impairing synaptic mechanisms of spatial learning and memory and resulting in cognitive decline.

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    • "For example, mice over-expressing NgR show impairment of hippocampus-dependent long-term memory (Karlén et al., 2009). Increased levels of hippocampal Nogo-A showing strong positive correlation with cognitive decline in aged rats (VanGuilder et al., 2011, 2012) and cognitive impairments in a mouse model of Alzheimer’s disease can be ameliorated by genetic deletion of Nogo-A (Masliah et al., 2010). The effects of decreased Nogo-A expression on the behavior of otherwise intact animals are less well explored. "
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    ABSTRACT: Decreased levels of Nogo-A-dependent signaling have been shown to affect behavior and cognitive functions. In Nogo-A knockout and knockdown laboratory rodents, behavioral alterations were observed, possibly corresponding with human neuropsychiatric diseases of neurodevelopmental origin, particularly schizophrenia. This study offers further insight into behavioral manifestations of Nogo-A knockdown in laboratory rats, focusing on spatial and non-spatial cognition, anxiety levels, circadian rhythmicity, and activity patterns. Demonstrated is an impairment of cognitive functions and behavioral flexibility in a spatial active avoidance task, while non-spatial memory in a step-through avoidance task was spared. No signs of anhedonia, typical for schizophrenic patients, were observed in the animals. Some measures indicated lower anxiety levels in the Nogo-A-deficient group. Circadian rhythmicity in locomotor activity was preserved in the Nogo-A knockout rats and their circadian period (tau) did not differ from controls. However, daily activity patterns were slightly altered in the knockdown animals. We conclude that a reduction of Nogo-A levels induces changes in CNS development, manifested as subtle alterations in cognitive functions, emotionality, and activity patterns.
    Frontiers in Behavioral Neuroscience 12/2014; 8:90. DOI:10.3389/fnbeh.2014.00090 · 3.27 Impact Factor
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    • "One of the most important matters for many individual as they “normally age” is a decline in cognitive functions [2,3]. Learning and memory deterioration affect nearly half of the aged population [4]. "
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    ABSTRACT: Background The aim of this study was to investigate the effects of a potent nitric oxide-guanylate cyclase activator, 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole (YC-1), on learning and memory functions in aged rats. Material/Methods Rats were divided into 2 groups as 4-month-old and 24-month-old rats. Rats received YC-1 (1 mg/kg/day) for 2 weeks long-term. Morris water maze (MWM) and passive avoidance (PA) tests were used to determine learning and memory functions. Results In the MWM test, there is a significant increase in the acquisition latency (1–4 days) of 24-month-old rats. There is a significant reduction in the “time spent in the escape platform’s quadrant” in 24-month-old rats compared to 4-month-old rats in the probe trial of the MWM test. YC-1 treatment reversed the reduction of the “time spent in the escape platform’s quadrant” of 24-month-old rats. In the PA test, there was no significant difference in the 1st-day latency of rats in all groups. On the 2nd day, retention latency significantly decreased in the 24-month-old rats compared to 4-month-olds. YC-1 reversed the diminished retention latency in 24-month-old rats. YC-1 treatment and aging did not affect results of the locomotor activity test or the foot-shock sensitivity test, suggesting our results were not due to a change in motor activity or disability of the animals. Conclusions Our findings suggest that activation of the NO-sGC-cGMP pathway plays an important role in spatial and emotional learning and memory functions in aged rats.
    08/2014; 20:130-137. DOI:10.12659/MSMBR.891064
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    • "In contrast, both genetic disruption of NgR1 (Hånell et al., 2010) or Nogo A/B (Marklund et al., 2009) was observed to impair cognitive outcome following TBI. Increased synaptosomal expression of Nogo-A, involved in the stabilization of hippocampal neurons (Zagrebelsky et al., 2010), was suggested a role in the cognitive decline that occurs with ageing (VanGuilder et al., 2012). In the present report, Nogo- A mRNA expression was increased although only at one day post-injury and the long-term regulation of the Nogo-A message is yet unknown. "
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    ABSTRACT: Purpose: When central nervous system axons are injured, regeneration is partly inhibited by myelin-associated inhibitors (MAIs). Following traumatic brain injury (TBI) in the rat, pharmacological neutralisation of the MAIs Nogo-A and myelin-associated glycoprotein (MAG) resulted in improved functional outcome. In contrast, genetic or pharmacological neutralization of the MAI receptors Nogo-66 receptor 1 (NgR1) or paired-immunoglobulin like receptor-B (PirB) showed an unaltered or impaired outcome following TBI in mice. The aim of the present study was thus to evaluate the MAI expression levels following TBI in mice. Methods: Quantitative reverse transcriptase PCR (qRT-PCR) was used to measure total RNA isolated from brains of young adult male C57BL/6 mice at one, three or seven days following controlled cortical impact TBI or sham injury. Hippocampal and neocortical tissue ipsi- and contralateral to the injury was analyzed for Nogo-A, oligodendrocyte-myelin glycoprotein (OMgp), MAG, and the MAI receptors PirB and NgR1, including its co-receptor Lingo1. Results: Compared to sham-injured controls, PirB neocortical expression was significantly upregulated at one day and NgR1 expression downregulated at seven days post-TBI. In the hippocampus, transcriptional upregulation was observed in Nogo-A (one day post-injury), MAG and PirB at seven days post-injury. In contrast, the hippocampal transcripts of NgR1 and Lingo1 were decreased at seven days post-injury. The expression of OMgp was unaltered at all time points post-injury. Conclusion: These results suggest that early dynamic changes in MAI gene expression occur following TBI in the mouse, particularly in the hippocampus, which may play an inhibitory role for post-injury regeneration and plasticity.
    Restorative neurology and neuroscience 07/2014; 32(5). DOI:10.3233/RNN-140419 · 2.49 Impact Factor
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