title: Rapid Nongenomic Glucocorticoid Actions in Male Mouse Hypothalamic Neuroendocrine Cells Are Dependent on the Nuclear Glucocorticoid Receptor.
abstract: Corticosteroids act classically via cognate nuclear receptors to regulate gene transcription; however, increasing evidence supports rapid, nontranscriptional corticosteroid actions via activation of membrane receptors. Using whole-cell patch clamp recordings in hypothalamic slices from male mouse genetic models, we tested for nongenomic glucocorticoid actions at glutamate and gamma aminobutyric acid (GABA) synapses in hypothalamic neuroendocrine cells, and for their dependence on the nuclear glucocorticoid receptor (GR). In enhanced green fluorescent protein-expressing CRH neurons of the paraventricular nucleus (PVN) and in magnocellular neurons of the PVN and supraoptic nucleus (SON), dexamethasone activated postsynaptic membrane-associated receptors and G protein signaling to elicit a rapid suppression of excitatory postsynaptic inputs, which was blocked by genetic deletion of type I cannabinoid receptors and a type I cannabinoid receptor antagonist. In magnocellular neurons, dexamethasone also elicited a rapid nitric oxide-dependent increase in inhibitory postsynaptic inputs. These data indicate a rapid, synapse-specific glucocorticoid-induced retrograde endocannabinoid signaling at glutamate synapses and nitric oxide signaling at GABA synapses. Unexpectedly, the rapid glucocorticoid effects on both excitatory and inhibitory synaptic transmission were lost with conditional deletion of GR in the PVN and SON in slices from a single minded-1-cre-directed conditional GR knockout mouse. Thus, the nongenomic glucocorticoid actions at glutamate and GABA synapses on PVN and SON neuroendocrine cells are dependent on the nuclear GR. The nuclear GR, therefore, is responsible for transducing the rapid steroid response at the membrane, or is either a critical component in the signaling cascade or regulates a critical component of the signaling cascade of a distinct membrane GR.
authors.affiliation: Departments of Cell and Molecular Biology (J.N., J.H., C.C., Z.J., N.R.G., J.G.T.) and Psychology (G.P.D.), and Neuroscience Program (G.P.D., J.G.T.), Tulane University, New Orleans, Louisiana 70118; and Departments of Pediatrics (L.J.M.) and Psychiatry and Behavioral Neuroscience (J.P.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45229.
authors.forename: Jebun
authors.initials: J
authors.lastname: Nahar
authors.affiliation: Departments of Cell and Molecular Biology (J.N., J.H., C.C., Z.J., N.R.G., J.G.T.) and Psychology (G.P.D.), and Neuroscience Program (G.P.D., J.G.T.), Tulane University, New Orleans, Louisiana 70118; and Departments of Pediatrics (L.J.M.) and Psychiatry and Behavioral Neuroscience (J.P.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45229.
authors.forename: Juhee
authors.initials: J
authors.lastname: Haam
authors.affiliation: Departments of Cell and Molecular Biology (J.N., J.H., C.C., Z.J., N.R.G., J.G.T.) and Psychology (G.P.D.), and Neuroscience Program (G.P.D., J.G.T.), Tulane University, New Orleans, Louisiana 70118; and Departments of Pediatrics (L.J.M.) and Psychiatry and Behavioral Neuroscience (J.P.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45229.
authors.forename: Chun
authors.initials: C
authors.lastname: Chen
authors.affiliation: Departments of Cell and Molecular Biology (J.N., J.H., C.C., Z.J., N.R.G., J.G.T.) and Psychology (G.P.D.), and Neuroscience Program (G.P.D., J.G.T.), Tulane University, New Orleans, Louisiana 70118; and Departments of Pediatrics (L.J.M.) and Psychiatry and Behavioral Neuroscience (J.P.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45229.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Departments of Cell and Molecular Biology (J.N., J.H., C.C., Z.J., N.R.G., J.G.T.) and Psychology (G.P.D.), and Neuroscience Program (G.P.D., J.G.T.), Tulane University, New Orleans, Louisiana 70118; and Departments of Pediatrics (L.J.M.) and Psychiatry and Behavioral Neuroscience (J.P.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45229.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Glatzer
authors.affiliation: Departments of Cell and Molecular Biology (J.N., J.H., C.C., Z.J., N.R.G., J.G.T.) and Psychology (G.P.D.), and Neuroscience Program (G.P.D., J.G.T.), Tulane University, New Orleans, Louisiana 70118; and Departments of Pediatrics (L.J.M.) and Psychiatry and Behavioral Neuroscience (J.P.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45229.
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Muglia
authors.affiliation: Departments of Cell and Molecular Biology (J.N., J.H., C.C., Z.J., N.R.G., J.G.T.) and Psychology (G.P.D.), and Neuroscience Program (G.P.D., J.G.T.), Tulane University, New Orleans, Louisiana 70118; and Departments of Pediatrics (L.J.M.) and Psychiatry and Behavioral Neuroscience (J.P.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45229.
authors.forename: Gary P
authors.initials: GP
authors.lastname: Dohanich
authors.affiliation: Departments of Cell and Molecular Biology (J.N., J.H., C.C., Z.J., N.R.G., J.G.T.) and Psychology (G.P.D.), and Neuroscience Program (G.P.D., J.G.T.), Tulane University, New Orleans, Louisiana 70118; and Departments of Pediatrics (L.J.M.) and Psychiatry and Behavioral Neuroscience (J.P.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45229.
authors.forename: James P
authors.initials: JP
authors.lastname: Herman
authors.affiliation: Departments of Cell and Molecular Biology (J.N., J.H., C.C., Z.J., N.R.G., J.G.T.) and Psychology (G.P.D.), and Neuroscience Program (G.P.D., J.G.T.), Tulane University, New Orleans, Louisiana 70118; and Departments of Pediatrics (L.J.M.) and Psychiatry and Behavioral Neuroscience (J.P.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45229.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Tasker
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055099:Neuroendocrine Cells / Q000187:drug effects* / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000502:physiology*; D013495:Supraoptic Nucleus / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics; D013997:Time Factors
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid