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Increased hippocampal NgR1 signaling machinery in aged rats with deficits of spatial cognition

Authors

  • Heather D. VanGuilder Starkey,

    1. Department of Pharmacology, R130 Hershey Center for Applied Research, Penn State College of Medicine, Hershey, PA, USA
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  • William E. Sonntag,

    1. Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
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  • Willard M. Freeman

    Corresponding author
    • Department of Pharmacology, R130 Hershey Center for Applied Research, Penn State College of Medicine, Hershey, PA, USA
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Correspondence: Dr W. M. Freeman, as above.

E-mail: wfreeman@psu.edu

Abstract

Myelin-associated inhibitor/NgR1 signaling has important roles in modulation of synaptic plasticity, with demonstrated effects on cognitive function. We have previously demonstrated that NgR1 and its ligands are upregulated in the hippocampus of aged rats with impaired spatial learning and memory, but it is unknown whether increased expression of these proteins indicates a potential increase in pathway signaling because NgR1 requires co-receptors for signal transduction through RhoA. Two co-receptor complexes have been identified to date, comprised of NgR1 and LINGO-1, and either p75 or TROY. In this study, we assessed the expression of LINGO-1, p75 and TROY, and the downstream effector RhoA in mature adult (12 months) and aged (26 months) male Fischer 344/Brown Norway hybrid rats classified as cognitively impaired or cognitively intact by Morris water maze testing. The hippocampal distribution of NgR1 and its co-receptors was assessed to determine whether receptor/co-receptor interaction, and therefore signaling through this pathway, is possible. Protein expression of LINGO-1, p75, TROY and RhoA was significantly elevated in cognitively impaired, but not intact, aged rats compared with mature adults, and expression levels correlated significantly with water maze performance. Co-localization of NgR1 with LINGO-1, p75 and TROY was observed in hippocampal neurons of aged, cognitively impaired rats. Further, expression profiles of NgR1 pathway components were demonstrated to classify rats as cognitively intact or cognitively impaired with high accuracy. Together, this suggests that hippocampal induction of this pathway is a conserved phenomenon in cognitive decline that may impair learning and memory by suppressing neuronal plasticity.

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