RT Journal Article
SR Electronic
T1 Schizophrenia-Like Features in Transgenic Mice Overexpressing Human HO-1 in the Astrocytic Compartment
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 10841
OP 10853
DO 10.1523/JNEUROSCI.6469-11.2012
VO 32
IS 32
A1 Wei Song
A1 Hillel Zukor
A1 Shih-Hsiung Lin
A1 Jacob Hascalovici
A1 Adrienne Liberman
A1 Ayda Tavitian
A1 Jeannie Mui
A1 Hojatollah Vali
A1 Xin-Kang Tong
A1 Sanjeev K. Bhardwaj
A1 Lalit K. Srivastava
A1 Edith Hamel
A1 Hyman M. Schipper
YR 2012
UL http://www.jneurosci.org/content/32/32/10841.abstract
AB 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.