An 'HO-1 Transducer' Model of Developmental and Degenerative Brain Disorders (S15.006)

OBJECTIVE: To ascertain whether overexpression of the stress protein, heme oxygenase-1 (HO-1) in astroglia transduces ambient risk factors into clinically-relevant patterns of developmental and degenerative neuropathology. BACKGROUND: 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. We previously showed that transfection of cultured astroglia with HMOX1 elicits cytopathological changes akin to those observed in human neurodevelopmental and degenerative disorders and renders nearby neurons vulnerable to oxidative injury. DESIGN/METHODS: GFAP.HMOX1 transgenic mice were engineered to overexpress human HO-1 in the astrocytic compartment. RESULTS: At 48 weeks of age, GFAP.HMOX1 transgenic mice exhibited subcortical oxidative stress and mitochondrial damage/autophagy; diminished neuronal reelin content (males); induction of Nurr1 and Pitx3; increased tyrosine hydroxylase and_α-synuclein expression; 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. CONCLUSIONS: 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. Supported by: CIHR. Disclosure: Dr. Tavitian has nothing to disclose. Dr. Song has nothing to disclose. Dr. Zukor has nothing to disclose. Dr. Lin has nothing to disclose. Dr. Hascalovici has nothing to disclose. Dr. Liberman has nothing to disclose. Dr. Mui has nothing to disclose. Dr. Vali has received personal compensation for activities with MD Robotics as as consultant. Dr. Tong has nothing to disclose. Dr. Bhardwaj has nothing to disclose. Dr. Srivastava has nothing to disclose. Dr. Hamel has nothing to disclose. Dr. Schipper has received personal compensation for activities with Caprion Pharmaceuticals Inc. and Osta Biotechnologies Inc. as consultant. Dr. Schipper has received compensation for serving on the board of Molecular Biometrics LLC, and Osta Biotech. Dr. Schipper has received research support from Osta Biotech Inc., Caprion Pharmaceuticals Inc. and Teva Neuroscience.