Ketamine-induced inhibition of glycogen synthase kinase-3 contributes to the augmentation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor signaling.
Sub-anesthetic doses of ketamine have been found to provide rapid antidepressant actions, indicating that the cellular signaling systems targeted by ketamine are potential sites for therapeutic intervention. Ketamine acts as an antagonist of N-methyl-D-aspartate (NMDA) receptors, and animal studies indicate that subsequent augmentation of signaling by α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors is critical for the antidepressant outcome.



In this study, we tested if the inhibitory effect of ketamine on glycogen synthase kinase-3 (GSK3) affected hippocampal cell-surface AMPA receptors using immunoblotting of membrane and synaptosomal extracts from wild-type and GSK3 knockin mice.



Treatment with an antidepressant dose of ketamine increased the hippocampal membrane level of the AMPA glutamate receptor (GluA)1 subunit, but did not alter the localization of GluA2, GluA3, or GluA4. This effect of ketamine was abrogated in GSK3 knockin mice expressing mutant GSK3 that cannot be inhibited by ketamine, demonstrating that ketamine-induced inhibition of GSK3 is necessary for up-regulation of cell surface AMPA GluA1 subunits. AMPA receptor trafficking is regulated by post-synaptic density-95 (PSD-95), a substrate for GSK3. Ketamine treatment decreased the hippocampal membrane level of phosphorylated PSD-95 on Thr-19, the target of GSK3 that promotes AMPA receptor internalization.



These results demonstrate that ketamine-induced inhibition of GSK3 causes reduced phosphorylation of PSD-95, diminishing the internalization of AMPA GluA1 subunits to allow for augmented signaling through AMPA receptors following ketamine treatment.
Department of Psychiatry and Behavioral Sciences and Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA. ebeurel@med.miami.edu.
Eléonore
E
Beurel
Department of Psychiatry and Behavioral Sciences and Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA.
Steven F
SF
Grieco
Department of Psychiatry and Behavioral Sciences and Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA.
Celeste
C
Amadei
Department of Psychiatry and Behavioral Sciences and Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA.
Kimberlee
K
Downey
Department of Psychiatry and Behavioral Sciences and Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA.
Richard S
RS
Jope
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001714:Bipolar Disorder / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007649:Ketamine / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D018091:Receptors, AMPA / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome
D000928:Antidepressive Agents; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; D018091:Receptors, AMPA; D007649:Ketamine; D038362:Glycogen Synthase Kinase 3; D051528:Guanylate Kinases

AMPA
; GSK3; PSD-95; depression; glycogen synthase kinase-3; ketamine
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