title: Structural abnormalities revealed by magnetic resonance imaging in rats prenatally exposed to methylazoxymethanol acetate parallel cerebral pathology in schizophrenia.
abstract: Schizophrenia is a highly familial, neurodevelopmental disorder that is associated with several neuropsychiatric, psychological, and neuropathological features. Although pharmacological animal models of dopaminergic and glutamatergic dysfunction have helped advance our understanding of the disease biology, there is a clear need for translational models that capture the neuropathological and functional manifestations associated with the intermediate phenotype and the clinical illness. Neuroimaging of preclinical neurodevelopmental approaches such as methylazoxymethanol acetate (MAM) exposure may afford a powerful translational tool to establish endpoints with greater congruency across animals and humans. Using in vivo volumetric magnetic resonance imaging (MRI), manganese-enhanced MRI, and diffusion tensor imaging (DTI), we investigated morphological and cytoarchitectural changes of brain structures in MAM-exposed rats, a neurodevelopmental model of schizophrenia. Compared to saline-exposed controls, MAM-exposed rats showed significant enlargement of lateral and third ventricles as well as reduced hippocampal volumes, which is consistent with findings observed in schizophrenia. In addition, DTI revealed that diffusion fractional anisotropy retrieved from corpus callosum and cingulum were significantly decreased in MAM-exposed rats, suggesting that demyelination occurred in these white-matter fiber tracts. Imaging findings were confirmed by conducting histological analysis using hematoxylin and eosin and Luxol fast blue stainings. In summary, structural abnormalities resulting from a MAM environmental challenge parallel cerebral pathology observed in schizophrenia. The MAM model incorporating noninvasive imaging techniques may therefore serve as an improved translational research tool for assessing new treatments for schizophrenia.
authors.affiliation: Advanced Technology, Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA. chih-liang.chin@abbott.com
authors.forename: Chih-Liang
authors.initials: CL
authors.lastname: Chin
authors.forename: Peter
authors.initials: P
authors.lastname: Curzon
authors.forename: Annette J
authors.initials: AJ
authors.lastname: Schwartz
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: O'Connor
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Rueter
authors.forename: Gerard B
authors.initials: GB
authors.lastname: Fox
authors.forename: Mark
authors.initials: M
authors.lastname: Day
authors.forename: Ana M
authors.initials: AM
authors.lastname: Basso
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001931:Brain Mapping; D002540:Cerebral Cortex / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology*; D002552:Cerebral Ventricles / Q000254:growth & development / Q000473:pathology; D003337:Corpus Callosum / Q000254:growth & development / Q000473:pathology; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D006624:Hippocampus / Q000254:growth & development / Q000473:pathology; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008746:Methylazoxymethanol Acetate / Q000633:toxicity*; D009498:Neurotoxins / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D009498:Neurotoxins; D008746:Methylazoxymethanol Acetate