title: Ketamine Strengthens CRF-Activated Amygdala Inputs to Basal Dendrites in mPFC Layer V Pyramidal Cells in the Prelimbic but not Infralimbic Subregion, A Key Suppressor of Stress Responses.
abstract: A single sub-anesthetic dose of ketamine, a short-acting NMDA receptor blocker, induces a rapid and prolonged antidepressant effect in treatment-resistant major depression. In animal models, ketamine (24 h) reverses depression-like behaviors and associated deficits in excitatory postsynaptic currents (EPSCs) generated in apical dendritic spines of layer V pyramidal cells of medial prefrontal cortex (mPFC). However, little is known about the effects of ketamine on basal dendrites. The basal dendrites of layer V cells receive an excitatory input from pyramidal cells of the basolateral amygdala (BLA), neurons that are activated by the stress hormone CRF. Here we found that CRF induces EPSCs in PFC layer V cells and that ketamine enhanced this effect through the mammalian target of rapamycin complex 1 synaptogenic pathway; the CRF-induced EPSCs required an intact BLA input and were generated primarily in basal dendrites. In contrast to its detrimental effects on apical dendritic structure and function, chronic stress did not induce a loss of CRF-induced EPSCs in basal dendrites, thereby creating a relative imbalance in favor of amygdala inputs. The effects of ketamine were complex: ketamine enhanced apical EPSC responses in all mPFC subregions, anterior cingulate (AC), prelimbic (PL), and infralimbic (IL) but enhanced CRF-induced EPSCs only in AC and PL-responses were unchanged in IL, a critical area for suppression of stress responses. We propose that by restoring the strength of apical inputs relative to basal amygdala inputs, especially in IL, ketamine would ameliorate the hypothesized disproportional negative influence of the amygdala in chronic stress and major depression.
authors.affiliation: Laboratory of Molecular Psychiatry, Department of Psychiatry, Connecticut Mental Health Center, Yale University School of Medicine, New Haven CT, USA.
authors.forename: Rong-Jian
authors.initials: RJ
authors.lastname: Liu
authors.affiliation: Laboratory of Molecular Psychiatry, Department of Psychiatry, Connecticut Mental Health Center, Yale University School of Medicine, New Haven CT, USA.
authors.forename: Kristie T
authors.initials: KT
authors.lastname: Ota
authors.affiliation: Laboratory of Molecular Psychiatry, Department of Psychiatry, Connecticut Mental Health Center, Yale University School of Medicine, New Haven CT, USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Dutheil
authors.affiliation: Laboratory of Molecular Psychiatry, Department of Psychiatry, Connecticut Mental Health Center, Yale University School of Medicine, New Haven CT, USA.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Duman
authors.affiliation: Laboratory of Molecular Psychiatry, Department of Psychiatry, Connecticut Mental Health Center, Yale University School of Medicine, New Haven CT, USA.
authors.forename: George K
authors.initials: GK
authors.lastname: Aghajanian
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000679:Amygdala / Q000166:cytology / Q000187:drug effects / Q000293:injuries / Q000502:physiology*; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D003712:Dendrites / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D066298:In Vitro Techniques; D007649:Ketamine / Q000494:pharmacology*; D008032:Limbic System / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D008297:Male; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000166:cytology*; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D003346:Corticotropin-Releasing Hormone