title: Cognitive Deficits, Changes in Synaptic Function, and Brain Pathology in a Mouse Model of Normal Aging(1,2,3).
abstract: Age is the main risk factor for sporadic Alzheimer's disease. Yet, cognitive decline in aged rodents has been less well studied, possibly due to concomitant changes in sensory or locomotor function that can complicate cognitive tests. We tested mice that were 3, 11, and 23 months old in cognitive, sensory, and motor measures, and postmortem measures of gliosis and neural activity (c-Fos). Hippocampal synaptic function was also examined. While age-related impairments were detectable in tests of spatial memory, greater age-dependent effects were observed in tests of associative learning [active avoidance (AA)]. Gross visual function was largely normal, but startle responses to acoustic stimuli decreased with increased age, possibly due to hearing impairments. Therefore, a novel AA variant in which light alone served as the conditioning stimuli was used. Age-related deficits were again observed. Mild changes in vision, as measured by optokinetic responses, were detected in 19- versus 4-month-old mice, but these were not correlated to AA performance. Thus, deficits in hearing or vision are unlikely to account for the observed deficits in cognitive measures. Increased gliosis was observed in the hippocampal formation at older ages. Age-related changes in neural function and plasticity were observed with decreased c-Fos in the dentate gyrus, and decreased synaptic strength and paired-pulse facilitation in CA1 slices. This work, which carefully outlines age-dependent impairments in cognitive and synaptic function, c-Fos activity, and gliosis during normal aging in the mouse, suggests robust translational measures that will facilitate further study of the biology of aging.
authors.affiliation: Department of Neuroscience, Genentech , South San Francisco, California 94080 ; Department of Psychiatry, University of California, San Diego , La Jolla, California 92093.
authors.forename: Martin
authors.initials: M
authors.lastname: Weber
authors.affiliation: Department of Neuroscience, Genentech , South San Francisco, California 94080.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Neuroscience, Genentech , South San Francisco, California 94080.
authors.forename: Jesse E
authors.initials: JE
authors.lastname: Hanson
authors.affiliation: Burke Medical Research Institute , White Plains, New York, 10605.
authors.forename: Nazia M
authors.initials: NM
authors.lastname: Alam
authors.affiliation: Department of Neuroscience, Genentech , South San Francisco, California 94080.
authors.forename: Hilda
authors.initials: H
authors.lastname: Solanoy
authors.affiliation: Department of Pathology, Genentech , South San Francisco, California 94080.
authors.forename: Hai
authors.initials: H
authors.lastname: Ngu
authors.affiliation: Department of Neuroscience, Genentech , South San Francisco, California 94080.
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Lauffer
authors.affiliation: Department of Neuroscience, Genentech , South San Francisco, California 94080.
authors.forename: Han H
authors.initials: HH
authors.lastname: Lin
authors.affiliation: Department of Neuroscience, Genentech , South San Francisco, California 94080.
authors.forename: Sara L
authors.initials: SL
authors.lastname: Dominguez
authors.affiliation: Department of Bioinformatics, Genentech , South San Francisco, California 94080.
authors.forename: Jens
authors.initials: J
authors.lastname: Reeder
authors.affiliation: Department of Bioinformatics, Genentech , South San Francisco, California 94080.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tom
authors.affiliation: Department of Neuroscience, Genentech , South San Francisco, California 94080.
authors.forename: Pascal
authors.initials: P
authors.lastname: Steiner
authors.affiliation: Department of Pathology, Genentech , South San Francisco, California 94080.
authors.forename: Oded
authors.initials: O
authors.lastname: Foreman
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, Burke Medical Research Institute , White Plains, New York 10605.
authors.forename: Glen T
authors.initials: GT
authors.lastname: Prusky
authors.affiliation: Department of Neuroscience, Genentech , South San Francisco, California 94080.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Scearce-Levie
keywords: age; c-Fos; cognition; gliosis; mice; synaptic function