title: Isoflurane unveils a critical role of glutamate transporter type 3 in regulating hippocampal GluR1 trafficking and context-related learning and memory in mice.
abstract: Glutamate transporter type 3 (EAAT3) may play a role in cognition. Isoflurane enhances EAAT3 trafficking to the plasma membrane. Thus, we used isoflurane to determine how EAAT3 might regulate learning and memory and the trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, such as GluR1, to the plasma membrane, a fundamental biochemical process for learning and memory. Here, isoflurane increased EAAT3 but did not change GluR1 levels in the plasma membrane of wild-type mouse hippocampus. Isoflurane increased protein phosphatase activity in the wild-type and EAAT3(-/-) mouse hippocampus. Also, isoflurane reduced GluR1 in the plasma membrane and decreased phospho-GluR1 in EAAT3(-/-) mice. The phosphatase inhibitor okadaic acid attenuated these effects. Finally, isoflurane inhibited context-related fear conditioning in EAAT3(-/-) mice but not in wild-type mice. Thus, isoflurane may increase GluR1 trafficking to the plasma membrane via EAAT3 and inhibit GluR1 trafficking via protein phosphatase. Lack of EAAT3 effects leads to decreased GluR1 trafficking and impaired cognition after isoflurane exposure in EAAT3(-/-) mice.
authors.affiliation: Department of Anesthesiology, University of Virginia, Charlottesville, VA 22908, United States; Department of Anesthesiology and Operation Center, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: J
authors.initials: J
authors.lastname: Cao
authors.affiliation: Department of Anesthesiology, University of Virginia, Charlottesville, VA 22908, United States; Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology and Operation Center, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: W
authors.initials: W
authors.lastname: Mi
authors.affiliation: Department of Anesthesiology, University of Virginia, Charlottesville, VA 22908, United States. Electronic address: zz3c@virginia.edu.
authors.forename: Z
authors.initials: Z
authors.lastname: Zuo
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D050580:Excitatory Amino Acid Transporter 3 / Q000378:metabolism*; D005971:Glutamates / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D008568:Memory / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D021381:Protein Transport; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018685:Anesthetics, Inhalation; D050580:Excitatory Amino Acid Transporter 3; D005971:Glutamates; D007530:Isoflurane; D018091:Receptors, AMPA; C493399:Slc1a1 protein, mouse
keywords: GluR1; cognition; glutamate transporter; hippocampus; isoflurane; trafficking