title: Hippocampal expression of myelin-associated inhibitors is induced with age-related cognitive decline and correlates with deficits of spatial learning and memory.
abstract: 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.
authors.affiliation: Department of Pharmacology, R130, Hershey Center for Applied Research, Penn State College of Medicine, Hershey, PA 17033, USA.
authors.forename: Heather D
authors.initials: HD
authors.lastname: Vanguilder
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Bixler
authors.forename: William E
authors.initials: WE
authors.lastname: Sonntag
authors.forename: Willard M
authors.initials: WM
authors.lastname: Freeman
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D003072:Cognition Disorders / Q000378:metabolism* / Q000473:pathology; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D008569:Memory Disorders / Q000378:metabolism* / Q000473:pathology; D009185:Myelin Proteins / Q000096:biosynthesis*; D018992:Myelin-Associated Glycoprotein / Q000096:biosynthesis; D000070798:Nogo Proteins; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344
chemical_list: D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D000070798:Nogo Proteins; C000603197:Rtn4 protein, rat