title: Glutamatergic regulation prevents hippocampal-dependent age-related cognitive decline through dendritic spine clustering.
abstract: The dementia of Alzheimer's disease (AD) results primarily from degeneration of neurons that furnish glutamatergic corticocortical connections that subserve cognition. Although neuron death is minimal in the absence of AD, age-related cognitive decline does occur in animals as well as humans, and it decreases quality of life for elderly people. Age-related cognitive decline has been linked to synapse loss and/or alterations of synaptic proteins that impair function in regions such as the hippocampus and prefrontal cortex. These synaptic alterations are likely reversible, such that maintenance of synaptic health in the face of aging is a critically important therapeutic goal. Here, we show that riluzole can protect against some of the synaptic alterations in hippocampus that are linked to age-related memory loss in rats. Riluzole increases glutamate uptake through glial transporters and is thought to decrease glutamate spillover to extrasynaptic NMDA receptors while increasing synaptic glutamatergic activity. Treated aged rats were protected against age-related cognitive decline displayed in nontreated aged animals. Memory performance correlated with density of thin spines on apical dendrites in CA1, although not with mushroom spines. Furthermore, riluzole-treated rats had an increase in clustering of thin spines that correlated with memory performance and was specific to the apical, but not the basilar, dendrites of CA1. Clustering of synaptic inputs is thought to allow nonlinear summation of synaptic strength. These findings further elucidate neuroplastic changes in glutamatergic circuits with aging and advance therapeutic development to prevent and treat age-related cognitive decline.
authors.affiliation: Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065; and apereira@rockefeller.edu mcewen@mail.rockefeller.edu john.morrison@mssm.edu.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Pereira
authors.affiliation: Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065; and.
authors.forename: Hilary K
authors.initials: HK
authors.lastname: Lambert
authors.affiliation: Fishberg Department of Neuroscience and Kastor Neurobiology of Aging Laboratories, The Friedman Brain Institute, and Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Yael S
authors.initials: YS
authors.lastname: Grossman
authors.affiliation: Fishberg Department of Neuroscience and Kastor Neurobiology of Aging Laboratories, The Friedman Brain Institute, and Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Dani
authors.initials: D
authors.lastname: Dumitriu
authors.affiliation: Fishberg Department of Neuroscience and Kastor Neurobiology of Aging Laboratories, The Friedman Brain Institute, and.
authors.forename: Rachel
authors.initials: R
authors.lastname: Waldman
authors.affiliation: Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065; and.
authors.forename: Sophia K
authors.initials: SK
authors.lastname: Jannetty
authors.affiliation: Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065; and.
authors.forename: Katina
authors.initials: K
authors.lastname: Calakos
authors.affiliation: Fishberg Department of Neuroscience and Kastor Neurobiology of Aging Laboratories, The Friedman Brain Institute, and.
authors.forename: William G
authors.initials: WG
authors.lastname: Janssen
authors.affiliation: Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065; and apereira@rockefeller.edu mcewen@mail.rockefeller.edu john.morrison@mssm.edu.
authors.forename: Bruce S
authors.initials: BS
authors.lastname: McEwen
authors.affiliation: Fishberg Department of Neuroscience and Kastor Neurobiology of Aging Laboratories, The Friedman Brain Institute, and Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029 apereira@rockefeller.edu mcewen@mail.rockefeller.edu john.morrison@mssm.edu.
authors.forename: John H
authors.initials: JH
authors.lastname: Morrison
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism* / Q000473:pathology; D003071:Cognition; D003712:Dendrites / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D008568:Memory; D018696:Neuroprotective Agents / Q000494:pharmacology; D017397:Prefrontal Cortex; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D019782:Riluzole / Q000494:pharmacology; D013569:Synapses / Q000378:metabolism / Q000473:pathology; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D019782:Riluzole
keywords: cognitive aging; dendritic spine clustering; glutamate; neuroplasticity; riluzole