title: Schizophrenia-like features in transgenic mice overexpressing human HO-1 in the astrocytic compartment.
abstract: Delineation of key molecules that act epigenetically to transduce diverse stressors into established patterns of disease would facilitate the advent of preventive and disease-modifying therapeutics for a host of neurological disorders. Herein, we demonstrate that selective overexpression of the stress protein heme oxygenase-1 (HO-1) in astrocytes of novel GFAP.HMOX1 transgenic mice results in subcortical oxidative stress and mitochondrial damage/autophagy; diminished neuronal reelin content (males); induction of Nurr1 and Pitx3 with attendant suppression of their targeting miRNAs, 145 and 133b; increased tyrosine hydroxylase and α-synuclein expression with downregulation of the targeting miR-7b of the latter; augmented dopamine and serotonin levels in basal ganglia; reduced D1 receptor binding in nucleus accumbens; axodendritic pathology and altered hippocampal cytoarchitectonics; impaired neurovascular coupling; attenuated prepulse inhibition (males); and hyperkinetic behavior. The GFAP.HMOX1 neurophenotype bears resemblances to human schizophrenia and other neurodevelopmental conditions and implicates glial HO-1 as a prime transducer of inimical (endogenous and environmental) influences on the development of monoaminergic circuitry. Containment of the glial HO-1 response to noxious stimuli at strategic points of the life cycle may afford novel opportunities for the effective management of human neurodevelopmental and neurodegenerative conditions.
authors.affiliation: Lady Davis Institute, Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.forename: Hillel
authors.initials: H
authors.lastname: Zukor
authors.forename: Shih-Hsiung
authors.initials: SH
authors.lastname: Lin
authors.forename: Jacob
authors.initials: J
authors.lastname: Hascalovici
authors.forename: Adrienne
authors.initials: A
authors.lastname: Liberman
authors.forename: Ayda
authors.initials: A
authors.lastname: Tavitian
authors.forename: Jeannie
authors.initials: J
authors.lastname: Mui
authors.forename: Hojatollah
authors.initials: H
authors.lastname: Vali
authors.forename: Xin-Kang
authors.initials: XK
authors.lastname: Tong
authors.forename: Sanjeev K
authors.initials: SK
authors.lastname: Bhardwaj
authors.forename: Lalit K
authors.initials: LK
authors.lastname: Srivastava
authors.forename: Edith
authors.initials: E
authors.lastname: Hamel
authors.forename: Hyman M
authors.initials: HM
authors.lastname: Schipper
mesh_terms: D000161:Acoustic Stimulation; D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism* / Q000648:ultrastructure; D001549:Benzamides / Q000493:pharmacokinetics; D001552:Benzazepines / Q000493:pharmacokinetics; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000473:pathology*; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000493:pharmacokinetics; D004622:Embryo, Mammalian; D004797:Enzyme-Linked Immunosorbent Assay; D020233:Gait Disorders, Neurologic / Q000209:etiology / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007266:Inhibition, Psychological; D017078:Laser-Doppler Flowmetry; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D000091042:Reelin Protein; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D055139:Sensory Gating / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014316:Tritium / Q000493:pharmacokinetics; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: D001549:Benzamides; D001552:Benzazepines; D015306:Biogenic Monoamines; D015259:Dopamine Agents; D005904:Glial Fibrillary Acidic Protein; D018398:Homeodomain Proteins; D035683:MicroRNAs; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D000091042:Reelin Protein; C534628:SCH 23390; D014157:Transcription Factors; D051844:alpha-Synuclein; C433629:homeobox protein PITX3; D014316:Tritium; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D014446:Tyrosine 3-Monooxygenase; D013482:Superoxide Dismutase; C000717127:RELN protein, human; C000717128:Reln protein, mouse; C030265:nemonapride