title: Activation of a ventral hippocampus-medial prefrontal cortex pathway is both necessary and sufficient for an antidepressant response to ketamine.
abstract: A single sub-anesthetic dose of ketamine exerts rapid and sustained antidepressant effects. Here, we examined the role of the ventral hippocampus (vHipp)-medial prefrontal cortex (mPFC) pathway in ketamine's antidepressant response. Inactivation of the vHipp with lidocaine prevented the sustained, but not acute, antidepressant-like effect of ketamine as measured by the forced swim test (FST). Moreover, optogenetic as well as pharmacogenetic specific activation of the vHipp-mPFC pathway using DREADDs (designer receptors exclusively activated by designer drugs) mimicked the antidepressant-like response to ketamine; importantly, this was pathway specific, in that activation of a vHipp to nucleus accumbens circuit did not do this. Furthermore, optogenetic inactivation of the vHipp/mPFC pathway at the time of FST completely reversed ketamine's antidepressant response. In addition, we found that a transient increase in TrkB receptor phosphorylation in the vHipp contributes to ketamine's sustained antidepressant response. These data demonstrate that activity in the vHipp-mPFC pathway is both necessary and sufficient for the antidepressant-like effect of ketamine.
authors.affiliation: Department of Pharmacology, Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: F R
authors.initials: FR
authors.lastname: Carreno
authors.affiliation: Department of Pharmacology, Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Donegan
authors.affiliation: Department of Pharmacology, Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Boley
authors.affiliation: Department of Pharmacology, Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Shah
authors.affiliation: Department of Pharmacology, Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: DeGuzman
authors.affiliation: Department of Pharmacology, Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, TX, USA.|South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Frazer
authors.affiliation: Department of Pharmacology, Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Lodge
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D003863:Depression / Q000188:drug therapy; D006624:Hippocampus / Q000378:metabolism; D007649:Ketamine / Q000378:metabolism* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D062308:Optogenetics / Q000379:methods; D017397:Prefrontal Cortex / Q000378:metabolism; D013550:Swimming
chemical_list: D000928:Antidepressive Agents; D007649:Ketamine