Schizophrenia-like features in transgenic mice overexpressing human HO-1 in the astrocytic compartment

• Published in: The Journal of neuroscience 2012-08, Vol.32 (32), p.10841-10853
• Main Authors: Song, Wei, Zukor, Hillel, Lin, Shih-Hsiung, Hascalovici, Jacob, Liberman, Adrienne, Tavitian, Ayda, Mui, Jeannie, Vali, Hojatollah, Tong, Xin-Kang, Bhardwaj, Sanjeev K, Srivastava, Lalit K, Hamel, Edith, Schipper, Hyman M
• Format: Article
• Language: English
• Subjects: Acoustic Stimulation; Age Factors; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Analysis of Variance; Animals; Animals, Newborn; Astrocytes - metabolism; Astrocytes - ultrastructure; Benzamides - pharmacokinetics; Benzazepines - pharmacokinetics; Biogenic Monoamines - metabolism; Brain - pathology; Chromatography, High Pressure Liquid; Disease Models, Animal; Dopamine Agents - pharmacokinetics; Embryo, Mammalian; Enzyme-Linked Immunosorbent Assay; Gait Disorders, Neurologic - etiology; Gait Disorders, Neurologic - genetics; Gene Expression Regulation, Developmental - genetics; Glial Fibrillary Acidic Protein - genetics; Glial Fibrillary Acidic Protein - metabolism; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Inhibition (Psychology); Laser-Doppler Flowmetry; Mice; Mice, Transgenic; MicroRNAs - genetics; MicroRNAs - metabolism; Nuclear Receptor Subfamily 4, Group A, Member 2 - genetics; Nuclear Receptor Subfamily 4, Group A, Member 2 - metabolism; Protein Binding - drug effects; Protein Binding - genetics; Receptors, Dopamine D1 - metabolism; Receptors, Dopamine D2 - metabolism; RNA, Messenger - metabolism; Schizophrenia - genetics; Schizophrenia - pathology; Schizophrenia - physiopathology; Sensory Gating - genetics; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Tritium - pharmacokinetics; Tyrosine 3-Monooxygenase - genetics; Tyrosine 3-Monooxygenase - metabolism
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/jneurosci.6469-11.2012

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.