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Manganese-enhanced magnetic resonance imaging reveals increased DOI-induced brain activity in a mouse model of schizophrenia

Malkova, Natalia V. and Gallagher, Joseph J. and Yu, Collin Z. and Jacobs, Russell E. and Patterson, Paul H. (2014) Manganese-enhanced magnetic resonance imaging reveals increased DOI-induced brain activity in a mouse model of schizophrenia. Proceedings of the National Academy of Sciences of the United States of America, 111 (24). E2492-E2500. ISSN 0027-8424. PMCID PMC4066472.

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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.

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URLURL TypeDescription DOIArticle material CentralArticle
Jacobs, Russell E.0000-0002-1382-8486
Additional Information:Copyright © 2014 National Academy of Sciences. Edited by Terrence J. Sejnowski, Salk Institute for Biological Studies, La Jolla, CA, and approved May 5, 2014 (received for review December 18, 2013). The authors acknowledge the kind assistance of A. Perles-Barbacaru, E,. Hsiao, J. Ko, W. Wu, and J. Zinnanti in reviewing the manuscript; L. Rodriguez for support and administrative assistance; M. Moore for technical help; E. Bearer for manuscript discussion; L. Sandoval, R. Sauza, and J. Rodriguez for maintaining the animals; and K. Piatkov for primer design. This research was supported by a National Institute of Mental Health Exceptional Unconventional Research Enabling Knowledge Acceleration award (MH086781; to P.H.P.), an Elizabeth Ross Fellowship for the Study of Mental Illness (to N.V.M.), a National Institute of Biomedical Imaging and Bioengineering award (R01 EB000993; to J.J.G. and R.E.J.), and a National Institute of Neurological Disorders and Stroke award (NS062184; to J.J.G. and R.E.J.). Author contributions: N.V.M. and P.H.P. designed research; N.V.M. and J.J.G. performed research; N.V.M., J.J.G., C.Z.Y., and R.E.J. analyzed data; and N.V.M., J.J.G., R.E.J., and P.H.P. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. This article contains supporting information online at
Errata:Correction for Malkova et al., Manganese-enhanced magnetic resonance imaging reveals increased DOI-induced brain activity in a mouse model of schizophrenia PNAS 2014 111 (39) 14307; published ahead of print September 2, 2014, doi:10.1073/pnas.1416478111
Funding AgencyGrant Number
Elizabeth Ross FellowshipUNSPECIFIED
NIHR01 EB000993
Subject Keywords:polyinosinic:polycytidylic acid; neurodevelopment; MEMRI; immediate early gene
Issue or Number:24
PubMed Central ID:PMC4066472
Record Number:CaltechAUTHORS:20140604-095439718
Persistent URL:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:46071
Deposited By: George Porter
Deposited On:04 Jun 2014 17:17
Last Modified:03 Oct 2019 06:40

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