Strategic Timing of Glial HMOX1 Expression Results in Either Schizophrenia-Like or Parkinsonian Behavior in Mice
| Autor: | Carmela Galindez, Marisa Cressatti, Adrienne Liberman, Wei Song, Ariana Z Turk, Adam Smart, Ayda Tavitian, Hyman M. Schipper |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Psychosis Levodopa Parkinson's disease Physiology Clinical Biochemistry Biochemistry 03 medical and health sciences medicine Molecular Biology Prepulse inhibition General Environmental Science 030102 biochemistry & molecular biology business.industry Parkinsonism Cell Biology medicine.disease Stereotypy (non-human) 030104 developmental biology Schizophrenia General Earth and Planetary Sciences medicine.symptom Hyperkinesia business Neuroscience medicine.drug |
| Zdroj: | Antioxidants & Redox Signaling. 32:1259-1272 |
| ISSN: | 1557-7716 1523-0864 |
| DOI: | 10.1089/ars.2019.7937 |
| Popis: | Aims: In this original research communication, we assess the impact of shifting the window of glial HMOX1 overexpression in mice from early-to-midlife to mid-to-late life, resulting in two disparate conditions modeling schizophrenia (SCZ) and Parkinson's disease (PD). Mesolimbic hyperdopaminergia is a widely accepted feature of SCZ, while nigrostriatal hypodopaminergia is the sine qua non of idiopathic PD. Although the advent of parkinsonian features in SCZ patients after treatment with antidopaminergic agents is intuitive, subtle features of parkinsonism commonly observed in young, drug-naive schizophrenics are not. Similarly, emergent psychosis in PD subjects receiving levodopa replacement is not unusual, whereas spontaneous hallucinosis in nonmedicated persons with idiopathic PD is enigmatic. Investigations using GFAP.HMOX1 mice may shed light on these clinical paradoxes. Results: Astroglial heme oxygenase-1 (HO-1) overexpression in mice throughout embryogenesis until 6 or 12 months of age resulted in hyperdopaminergia, hyperkinesia/stereotypy ameliorated with clozapine, deficient prepulse inhibition of the acoustic startle response, reduced preference for social novelty, impaired nest building, and cognitive dysfunction reminiscent of SCZ. On the contrary, astroglial HO-1 overexpression between 8.5 and 19 months of age yielded a PD-like behavioral phenotype with hypodopaminergia, altered gait, locomotor incoordination, and reduced olfaction. Innovation: We conjecture that region-specific disparities in the susceptibility of dopaminergic and other circuitry to the trophic and degenerative influences of glial HMOX1 induction may permit the concomitant expression of mixed SCZ and PD traits within affected individuals. Conclusion: Elucidation of these converging mechanisms may (i) help better understand disease pathogenesis and (ii) identify HO-1 as a potential therapeutic target in neurodevelopmental and neurodegenerative disorders. |
| Databáze: | OpenAIRE |
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