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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acoustic Stimulation
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Age Factors
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Analysis of Variance
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Animals
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Animals, Newborn
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Astrocytes / metabolism*
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Astrocytes / ultrastructure
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Benzamides / pharmacokinetics
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Benzazepines / pharmacokinetics
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Biogenic Monoamines / metabolism
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Brain / pathology*
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Chromatography, High Pressure Liquid
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Disease Models, Animal
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Dopamine Agents / pharmacokinetics
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Embryo, Mammalian
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Enzyme-Linked Immunosorbent Assay
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Gait Disorders, Neurologic / etiology
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Gait Disorders, Neurologic / genetics
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Gene Expression Regulation, Developmental / genetics*
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Glial Fibrillary Acidic Protein / genetics
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Glial Fibrillary Acidic Protein / metabolism
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Heme Oxygenase-1 / genetics
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Heme Oxygenase-1 / metabolism*
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Inhibition, Psychological
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Laser-Doppler Flowmetry
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Mice
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Mice, Transgenic
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MicroRNAs / genetics
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MicroRNAs / metabolism
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Nuclear Receptor Subfamily 4, Group A, Member 2 / genetics
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Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism
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Protein Binding / drug effects
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Protein Binding / genetics
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RNA, Messenger / metabolism
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Receptors, Dopamine D1 / metabolism
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Receptors, Dopamine D2 / metabolism
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Reelin Protein
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Schizophrenia / genetics*
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Schizophrenia / pathology*
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Schizophrenia / physiopathology
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Sensory Gating / genetics
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Superoxide Dismutase / genetics
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Superoxide Dismutase / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Tritium / pharmacokinetics
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Tyrosine 3-Monooxygenase / genetics
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Tyrosine 3-Monooxygenase / metabolism
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alpha-Synuclein / genetics
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alpha-Synuclein / metabolism
Substances
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Benzamides
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Benzazepines
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Biogenic Monoamines
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Dopamine Agents
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Glial Fibrillary Acidic Protein
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Homeodomain Proteins
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MicroRNAs
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Nr4a2 protein, mouse
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Nuclear Receptor Subfamily 4, Group A, Member 2
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RNA, Messenger
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Receptors, Dopamine D1
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Receptors, Dopamine D2
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Reelin Protein
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SCH 23390
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Transcription Factors
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alpha-Synuclein
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homeobox protein PITX3
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Tritium
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HMOX1 protein, human
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Heme Oxygenase-1
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Tyrosine 3-Monooxygenase
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Superoxide Dismutase
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RELN protein, human
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Reln protein, mouse
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nemonapride