title: Longitudinal Effects of Ketamine on Dendritic Architecture In Vivo in the Mouse Medial Frontal Cortex.
abstract: A single subanesthetic dose of ketamine, an NMDA receptor antagonist, leads to fast-acting antidepressant effects. In rodent models, systemic ketamine is associated with higher dendritic spine density in the prefrontal cortex, reflecting structural remodeling that may underlie the behavioral changes. However, turnover of dendritic spines is a dynamic process in vivo, and the longitudinal effects of ketamine on structural plasticity remain unclear. The purpose of the current study is to use subcellular resolution optical imaging to determine the time course of dendritic alterations in vivo following systemic ketamine administration in mice. We used two-photon microscopy to visualize repeatedly the same set of dendritic branches in the mouse medial frontal cortex (MFC) before and after a single injection of ketamine or saline. Compared to controls, ketamine-injected mice had higher dendritic spine density in MFC for up to 2 weeks. This prolonged increase in spine density was driven by an elevated spine formation rate, and not by changes in the spine elimination rate. A fraction of the new spines following ketamine injection was persistent, which is indicative of functional synapses. In a few cases, we also observed retraction of distal apical tuft branches on the day immediately after ketamine administration. These results indicate that following systemic ketamine administration, certain dendritic inputs in MFC are removed immediately, while others are added gradually. These dynamic structural modifications are consistent with a model of ketamine action in which the net effect is a rebalancing of synaptic inputs received by frontal cortical neurons.
authors.affiliation: Department of Psychiatry, Yale University , New Haven, Connecticut 06511.
authors.forename: Victoria
authors.initials: V
authors.lastname: Phoumthipphavong
authors.affiliation: Department of Psychiatry, Yale University , New Haven, Connecticut 06511.
authors.forename: Florent
authors.initials: F
authors.lastname: Barthas
authors.affiliation: Department of Psychiatry, Yale University , New Haven, Connecticut 06511.
authors.forename: Samantha
authors.initials: S
authors.lastname: Hassett
authors.affiliation: Department of Psychiatry, Yale University, New Haven, Connecticut 06511; Department of Neuroscience, Yale University, New Haven, Connecticut 06511.
authors.forename: Alex C
authors.identifier: 0000-0003-2169-1667
authors.initials: AC
authors.lastname: Kwan
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D003712:Dendrites / Q000187:drug effects*; D049229:Dendritic Spines / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D005625:Frontal Lobe / Q000166:cytology* / Q000000981:diagnostic imaging; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007649:Ketamine / Q000494:pharmacology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D018800:Thy-1 Antigens / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: D001426:Bacterial Proteins; D018691:Excitatory Amino Acid Antagonists; D008164:Luminescent Proteins; D018800:Thy-1 Antigens; C054562:yellow fluorescent protein, Bacteria; D049452:Green Fluorescent Proteins; D007649:Ketamine
keywords: dendrites; dendritic spines; frontal cortex; ketamine; structural plasticity; two-photon microscopy