title: Riluzole rescues glutamate alterations, cognitive deficits, and tau pathology associated with P301L tau expression.
abstract: Hyperexcitability of the hippocampus is a commonly observed phenomenon in the years preceding a diagnosis of Alzheimer's disease (AD). Our previous work suggests a dysregulation in glutamate neurotransmission may mediate this hyperexcitability, and glutamate dysregulation correlates with cognitive deficits in the rTg(TauP301L)4510 mouse model of AD. To determine whether improving glutamate regulation would attenuate cognitive deficits and AD-related pathology, TauP301L mice were treated with riluzole (~ 12.5 mg/kg/day p.o.), an FDA-approved drug for amyotrophic lateral sclerosis that lowers extracellular glutamate levels. Riluzole-treated TauP301L mice exhibited improved performance in the water radial arm maze and the Morris water maze, associated with a decrease in glutamate release and an increase in glutamate uptake in the dentate gyrus, cornu ammonis 3 (CA3), and cornu ammonis 1 (CA1) regions of the hippocampus. Riluzole also attenuated the TauP301L-mediated increase in hippocampal vesicular glutamate transporter 1, which packages glutamate into vesicles and influences glutamate release; and the TauP301L-mediated decrease in hippocampal glutamate transporter 1, the major transporter responsible for removing glutamate from the extracellular space. The TauP301L-mediated reduction in PSD-95 expression, a marker of excitatory synapses in the hippocampus, was also rescued by riluzole. Riluzole treatment reduced total levels of tau, as well as the pathological phosphorylation and conformational changes in tau associated with the P301L mutation. These findings open new opportunities for the development of clinically applicable therapeutic approaches to regulate glutamate in vulnerable circuits for those at risk for the development of AD.
authors.affiliation: Behavioral Neuroscience, Department of Psychology, West Virginia University, Morgantown, West Virginia, USA.
authors.forename: Holly C
authors.initials: HC
authors.lastname: Hunsberger
authors.affiliation: Behavioral Neuroscience, Department of Psychology, West Virginia University, Morgantown, West Virginia, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Weitzner
authors.affiliation: Behavioral Neuroscience, Department of Psychology, West Virginia University, Morgantown, West Virginia, USA.
authors.forename: Carolyn C
authors.initials: CC
authors.lastname: Rudy
authors.affiliation: Behavioral Neuroscience, Department of Psychology, West Virginia University, Morgantown, West Virginia, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Hickman
authors.affiliation: Department of Biology, West Virginia University, Morgantown, West Virginia, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Libell
authors.affiliation: Department of Biology, West Virginia University, Morgantown, West Virginia, USA.
authors.forename: Rebecca R
authors.initials: RR
authors.lastname: Speer
authors.affiliation: Center for Microelectrode Technology (CenMeT), Department of Anatomy and Neurobiology, University of Kentucky Health Sciences Center, Lexington, Kentucky, USA.
authors.forename: Greg A
authors.initials: GA
authors.lastname: Gerhardt
authors.affiliation: Behavioral Neuroscience, Department of Psychology, West Virginia University, Morgantown, West Virginia, USA.|Center for Neuroscience, West Virginia University, Morgantown, West Virginia, USA.|Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, West Virginia, USA.|Drug Discovery & Development Department, School of Pharmacy, Auburn University, Auburn, Alabama.
authors.forename: Miranda N
authors.initials: MN
authors.lastname: Reed
mesh_terms: D000544:Alzheimer Disease / Q000517:prevention & control / Q000523:psychology; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D003072:Cognition Disorders / Q000517:prevention & control* / Q000523:psychology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019782:Riluzole / Q000494:pharmacology*; D013569:Synapses / Q000187:drug effects / Q000473:pathology; D024801:Tauopathies / Q000517:prevention & control* / Q000523:psychology*; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D016875:tau Proteins / Q000096:biosynthesis*
chemical_list: D018691:Excitatory Amino Acid Antagonists; C054369:MAPT protein, human; D018696:Neuroprotective Agents; D050598:Vesicular Glutamate Transport Protein 1; D016875:tau Proteins; D018698:Glutamic Acid; D019782:Riluzole
keywords: Alzheimer's disease; glutamate clearance; hippocampus; memory; riluzole; tau