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

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 to 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.

Dynamic Nature of the p75 Neurotrophin Receptor in Response to Injury and Disease

“…Importantly, stimulation of hippocampal slices with proBDNF enhanced long-term depression in a p75 NTR -dependent fashion indicating that p75 NTR plays a normal role in the regulation of synaptic plasticity, possibly via increased expression of NR2B(Woo et al, 2005) or shifts in the AMPA receptor GluR2/3 balance(Rosch et al, 2005). In vivo studies supported these observations by showing that p75 NTR expression in adult hippocampal neurons was increased in aged rats with cognitive impairment(VanGuilder Starkey et al, 2013). Thus, qualitative shifts in plastic neural responses based on receptor availability may influence the efficiency of learning and memory processes.…”

Expression of NgR1-Antagonizing Proteins Decreases with Aging and Cognitive Decline in Rat Hippocampus

“…Behavioral stratification of subjects and dissection of CA1, CA3 and DG subregions has been described in detail elsewhere (VanGuilder et al, 2011a, 2012; VanGuilder Starkey et al, 2012, 2013.) All animal experiments were performed in accordance with IACUC and AALAC approved procedures. Briefly, mature adult (12 months) and aged (26 months) male Fischer 344 × Brown Norway (F1) hybrid rats were purchased from the National Institute on Aging rodent colony maintained by Harlan Industries (Indianapolis, IN) and housed singly in the OUHSC Reynolds Oklahoma Center on Aging barrier facility, with water and food (Purina Mills, Richmond, IN) freely available.…”

“…Briefly, mature adult (12 months) and aged (26 months) male Fischer 344 × Brown Norway (F1) hybrid rats were purchased from the National Institute on Aging rodent colony maintained by Harlan Industries (Indianapolis, IN) and housed singly in the OUHSC Reynolds Oklahoma Center on Aging barrier facility, with water and food (Purina Mills, Richmond, IN) freely available. Rats were tested for hippocampal spatial learning and memory ability by Morris water maze and aged rats were classified as cognitively intact or impaired relative to the mature adult group based on mean proximity to the escape platform location during probe trials (VanGuilder et al, 2011a, 2012; VanGuilder Starkey et al, 2012, 2013).…”

“…Anatomical, biochemical and electrophysiological assessments demonstrate an inverse relationship between MAI/NgR1 pathway expression and hippocampal spine density, efficacy of activity-dependent synaptic plasticity, and spatial learning and memory (Zagrebelsky et al, 2005, Lee et al, 2008, Karlen et al, 2009, Raiker et al, 2010, Delekate et al, 2011). We have previously demonstrated the significant hippocampal upregulation of the MAI ligands Nogo-A, MAG, and OMgp, the NgR1 receptor and its signal-transducing co-receptors in a naturally occurring rat model of human age-related cognitive decline (VanGuilder et al, 2011b, 2012; VanGuilder et al, 2013) (Supplemental Table 1). Interestingly, induction of MAI/NgR1 pathway components occurs specifically in cognitively impaired, but not cognitively intact, aged rats phenotyped for hippocampal cognitive function, and is highly conserved within individual subjects, suggesting an important role of MAI/NgR1-mediated suppression of synaptic plasticity in impaired spatial learning and memory.…”

Insulin-like growth factor-1 in CNS and cerebrovascular aging

“…We have previously reported an increase in myelination proteins in the hippocampus of cognitively impaired aged rats (VanGuilder et al, 2011b, 2012; VanGuilder Starkey et al, 2013b). This up-regulation included an increase in myelin-associated proteins on the surface of oligodendrocytes and neurons, including myelin-associated glycoprotein (MAG), myelin-oligodendrocyte glycoprotein (MOG), and neurite outgrowth inhibitor (NOGO-A), as well as an increase in the neuronal receptor complexes for these myelination proteins, Nogo-66 receptor 1 (NgR1) and co-receptors p75, TROY (a member of the Tumor necrosis factor receptor superfamily, member 19, also known as TNFRSF19) and LRR and Ig domain-containing, Nogo Receptor-interacting protein (LINGO-1) (VanGuilder et al, 2011b, 2012; VanGuilder Starkey et al, 2013b). Furthermore, we reported an age-related decrease in antagonists of the NgR1 myelination pathway (VanGuilder Starkey et al, 2013a).…”