title: Optogenetic stimulation of infralimbic PFC reproduces ketamine's rapid and sustained antidepressant actions.
abstract: Ketamine produces rapid and sustained antidepressant actions in depressed patients, but the precise cellular mechanisms underlying these effects have not been identified. Here we determined if modulation of neuronal activity in the infralimbic prefrontal cortex (IL-PFC) underlies the antidepressant and anxiolytic actions of ketamine. We found that neuronal inactivation of the IL-PFC completely blocked the antidepressant and anxiolytic effects of systemic ketamine in rodent models and that ketamine microinfusion into IL-PFC reproduced these behavioral actions of systemic ketamine. We also found that optogenetic stimulation of the IL-PFC produced rapid and long-lasting antidepressant and anxiolytic effects and that these effects are associated with increased number and function of spine synapses of layer V pyramidal neurons. The results demonstrate that ketamine infusions or optogenetic stimulation of IL-PFC are sufficient to produce long-lasting antidepressant behavioral and synaptic responses similar to the effects of systemic ketamine administration.
authors.affiliation: Laboratory of Molecular Psychiatry, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508.
authors.forename: Manabu
authors.initials: M
authors.lastname: Fuchikami
authors.affiliation: Laboratory of Molecular Psychiatry, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Laboratory of Molecular Psychiatry, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508.
authors.forename: Rongjian
authors.initials: R
authors.lastname: Liu
authors.affiliation: Laboratory of Molecular Psychiatry, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Wohleb
authors.affiliation: Laboratory of Molecular Psychiatry, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508.
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Land
authors.affiliation: Laboratory of Molecular Psychiatry, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DiLeone
authors.affiliation: Laboratory of Molecular Psychiatry, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508.
authors.forename: George K
authors.initials: GK
authors.lastname: Aghajanian
authors.affiliation: Laboratory of Molecular Psychiatry, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508 ronald.duman@yale.edu.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Duman
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D007649:Ketamine / Q000494:pharmacology*; D008032:Limbic System / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D062308:Optogenetics; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000928:Antidepressive Agents; D007649:Ketamine
keywords: antidepressant; glutamate; neural depolarization; prefrontal cortex; synapse