title: Adiponectin regulates contextual fear extinction and intrinsic excitability of dentate gyrus granule neurons through AdipoR2 receptors.
abstract: Post-traumatic stress disorder (PTSD) is characterized by exaggerated fear expression and impaired fear extinction. The underlying molecular and cellular mechanisms of PTSD are largely unknown. The current pharmacological and non-pharmacological treatments for PTSD are either ineffective or temporary with high relapse rates. Here we report that adiponectin-deficient mice exhibited normal contextual fear conditioning but displayed slower extinction learning. Infusions of adiponectin into the dentate gyrus (DG) of the hippocampus in fear-conditioned mice facilitated extinction of contextual fear. Whole-cell patch-clamp recordings in brain slices revealed that intrinsic excitability of DG granule neurons was enhanced by adiponectin deficiency and suppressed after treatment with the adiponectin mimetic AdipoRon, which were associated with increased input resistance and hyperpolarized resting membrane potential, respectively. Moreover, deletion of AdipoR2, but not AdipoR1 in the DG, resulted in augmented fear expression and reduced extinction, accompanied by intrinsic hyperexcitability of DG granule neurons. Adiponectin and AdipoRon failed to induce facilitation of fear extinction and elicit inhibition of intrinsic excitability of DG neurons in AdipoR2 knockout mice. These results indicated that adiponectin action via AdipoR2 was both necessary and sufficient for extinction of contextual fear and intrinsic excitability of DG granule neurons, implying that enhancing or dampening DG neuronal excitability may cause resistance to or facilitation of extinction. Therefore, our findings provide a functional link between adiponectin/AdipoR2 activation, DG neuronal excitability and contextual fear extinction, and suggest that targeting adiponectin/AdipoR2 may be used to strengthen extinction-based exposure therapies for PTSD.
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: D
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Institute for Metabolic and Neuropsychiatric Disorders, Binzhou Medical University, Binzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Garza
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: X
authors.initials: X
authors.lastname: Fang
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: P E
authors.initials: PE
authors.lastname: Scherer
authors.affiliation: Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Brenner
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Institute for Metabolic and Neuropsychiatric Disorders, Binzhou Medical University, Binzhou, China.|Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: X-Y
authors.initials: XY
authors.lastname: Lu
mesh_terms: D000200:Action Potentials / Q000502:physiology; D052242:Adiponectin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003214:Conditioning, Classical / Q000502:physiology; D018891:Dentate Gyrus / Q000378:metabolism*; D004195:Disease Models, Animal; D005108:Extinction, Psychological / Q000502:physiology; D005239:Fear / Q000502:physiology; D005260:Female; D006624:Hippocampus; D007858:Learning / Q000502:physiology; D008032:Limbic System; D008297:Male; D008564:Membrane Potentials; D008661:Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000502:physiology; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000502:physiology; D054419:Receptors, Adiponectin / Q000378:metabolism*; D013313:Stress Disorders, Post-Traumatic / Q000378:metabolism
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D054419:Receptors, Adiponectin; C475421:adiponectin receptor 2, mouse