title: Riluzole partially rescues age-associated, but not LPS-induced, loss of glutamate transporters and spatial memory.
abstract: Impaired memory may result from synaptic glutamatergic dysregulation related to chronic neuroinflammation. GLT1 is the primary excitatory amino acid transporter responsible for regulating extracellular glutamate levels in the hippocampus. We tested the hypothesis that if impaired spatial memory results from increased extracellular glutamate due to age or experimentally induced chronic neuroinflammation in the hippocampus, then pharmacological augmentation of the glutamate transporter GLT1 will attenuate deficits in a hippocampal-dependent spatial memory task. The profile of inflammation-related genes and proteins associated with normal aging, or chronic neuroinflammation experimentally-induced via a four-week LPS infusion into the IV(th) ventricle, were correlated with performance in the Morris water maze following treatment with Riluzole, a drug that can enhance glutamate clearance by increasing GLT1 expression. Age-associated inflammation was qualitatively different from LPS-induced neuro-inflammation in young rats. LPS produced a pro-inflammatory phenotype characterized by increased IL-1ß expression in the hippocampus, whereas aging was not associated with a strong central pro-inflammatory response but with a mixed peripheral immune phenotype. Riluzole attenuated the spatial memory impairment, the elevation of serum cytokines and the decrease in GLT1 gene expression in Aged rats, but had no effect on young rats infused with LPS. Our findings highlight the therapeutic potential of reducing glutamatergic function upon memory impairment in neurodegenerative diseases associated with aging.
authors.affiliation: Department of Psychology, Ohio State University, 1835 Neil Avenue, Columbus, OH, 43210, USA.
authors.forename: Holly M
authors.initials: HM
authors.lastname: Brothers
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bardou
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Hopp
authors.forename: Roxanne M
authors.initials: RM
authors.lastname: Kaercher
authors.forename: Angela W
authors.initials: AW
authors.lastname: Corona
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Fenn
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Godbout
authors.forename: Gary L
authors.initials: GL
authors.lastname: Wenk
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D050491:Glutamate Plasma Membrane Transport Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019782:Riluzole / Q000494:pharmacology*
chemical_list: D050491:Glutamate Plasma Membrane Transport Proteins; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D019782:Riluzole