title: Manganese-enhanced magnetic resonance imaging reveals increased DOI-induced brain activity in a mouse model of schizophrenia.
abstract: Maternal infection during pregnancy increases the risk for schizophrenia in offspring. In rodent models, maternal immune activation (MIA) yields offspring with schizophrenia-like behaviors. None of these behaviors are, however, specific to schizophrenia. The presence of hallucinations is a key diagnostic symptom of schizophrenia. In mice, this symptom can be defined as brain activation in the absence of external stimuli, which can be mimicked by administration of hallucinogens. We find that, compared with controls, adult MIA offspring display an increased stereotypical behavioral response to the hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI), an agonist for serotonin receptor 2A (5-HT2AR). This may be explained by increased levels of 5-HT2AR and downstream signaling molecules in unstimulated MIA prefrontal cortex (PFC). Using manganese-enhanced magnetic resonance imaging to identify neuronal activation elicited by DOI administration, we find that, compared with controls, MIA offspring exhibit a greater manganese (Mn(2+)) accumulation in several brain areas, including the PFC, thalamus, and striatum. The parafascicular thalamic nucleus, which plays the role in the pathogenesis of hallucinations, is activated by DOI in MIA offspring only. Additionally, compared with controls, MIA offspring demonstrate higher DOI-induced expression of early growth response protein 1, cyclooxygenase-2, and brain-derived neurotrophic factor in the PFC. Chronic treatment with the 5-HT2AR antagonist ketanserin reduces DOI-induced head twitching in MIA offspring. Thus, the MIA mouse model can be successfully used to investigate activity induced by DOI in awake, behaving mice. Moreover, manganese-enhanced magnetic resonance imaging is a useful, noninvasive method for accurately measuring this type of activity.
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125; and malkova@caltech.edu.
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Malkova
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125; and.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Gallagher
authors.affiliation: School of Pharmacy, University of California, San Francisco, CA 94143-0622.
authors.forename: Collin Z
authors.initials: CZ
authors.lastname: Yu
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125; and.
authors.forename: Russell E
authors.initials: RE
authors.lastname: Jacobs
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125; and.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Patterson
mesh_terms: D000662:Amphetamines / Q000737:chemistry*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001931:Brain Mapping; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003287:Contrast Media / Q000737:chemistry*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D006213:Hallucinogens / Q000737:chemistry*; D007650:Ketanserin / Q000737:chemistry; D008024:Ligands; D008279:Magnetic Resonance Imaging; D008297:Male; D008345:Manganese / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects; D011070:Poly I-C / Q000737:chemistry; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D012307:Risk Factors; D012559:Schizophrenia / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D000662:Amphetamines; D019208:Brain-Derived Neurotrophic Factor; D003287:Contrast Media; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D006213:Hallucinogens; D008024:Ligands; D044402:Receptor, Serotonin, 5-HT2A; D008345:Manganese; D007650:Ketanserin; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D011070:Poly I-C; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine
keywords: MEMRI; immediate early gene; neurodevelopment; polyinosinic:polycytidylic acid