title: Ketamine Corrects Stress-Induced Cognitive Dysfunction through JAK2/STAT3 Signaling in the Orbitofrontal Cortex.
abstract: Deficits in cognitive flexibility are prominent in stress-related psychiatric disorders, including depression. Ketamine has rapid antidepressant efficacy, but it is unknown if ketamine improves cognitive symptoms. In rats, 2 weeks chronic intermittent cold (CIC) stress impairs reversal learning, a form of cognitive flexibility mediated by the orbitofrontal cortex (OFC) that we have used previously to model cognitive dysfunction in depression. We have shown that activating JAK2/STAT3 signaling in the OFC rescued the CIC stress-induced reversal learning deficit. Thus, in the present study we determined whether ketamine also corrects the stress-induced reversal learning deficit, and if JAK2/STAT3 signaling is involved in this effect. A single injection of ketamine (10 mg/kg, i.p.) 24 h prior to testing rescued the CIC stress-induced reversal learning deficit. CIC stress decreased JAK2 phosphorylation in the OFC, and ketamine restored pJAK2 levels within 2 h post injection. The JAK2 inhibitor AG490 given systemically or into the OFC at the time of ketamine injection prevented its beneficial effect on reversal learning. We then tested the role of JAK2/STAT3 in ketamine-induced plasticity in the OFC. Ketamine depressed local field potentials evoked in the OFC by excitatory thalamic afferent stimulation, and this was prevented by JAK2 inhibition in the OFC. Further, in both the OFC and primary cortical neurons in culture, ketamine increased expression of the neural plasticity-related protein Arc, and this was prevented by JAK2 inhibition. These results suggest that the JAK2/STAT3 signaling pathway is a novel mechanism by which ketamine exerts its therapeutic effects on stress-induced cognitive dysfunction in the OFC.
authors.affiliation: Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Patton
authors.affiliation: Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lodge
authors.affiliation: Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Morilak
authors.affiliation: Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Milena
authors.initials: M
authors.lastname: Girotti
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D060825:Cognitive Dysfunction / Q000188:drug therapy* / Q000209:etiology; D003598:Cytoskeletal Proteins / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000187:drug effects*; D007649:Ketamine / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects*; D017397:Prefrontal Cortex / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012193:Reversal Learning / Q000187:drug effects*; D050796:STAT3 Transcription Factor / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D013315:Stress, Psychological / Q000150:complications*; D020032:Tyrphostins / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000928:Antidepressive Agents; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D020032:Tyrphostins; C092069:activity regulated cytoskeletal-associated protein; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D007649:Ketamine; C507927:Jak2 protein, rat; D053614:Janus Kinase 2