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Activation of the maternal immune system alters cerebellar development in the offspring

Shi, Limin and Smith, Stephen E. P. and Malkova, Natalia and Tse, Doris and Su, Yixuan and Patterson, Paul H. (2009) Activation of the maternal immune system alters cerebellar development in the offspring. Brain, Behavior, and Immunity, 23 (1). pp. 116-123. ISSN 1090-2139. PMCID PMC2614890. doi:10.1016/j.bbi.2008.07.012.

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A common pathological finding in autism is a localized deficit in Purkinje cells (PCs). Cerebellar abnormalities have also been reported in schizophrenia. Using a mouse model that exploits a known risk factor for these disorders, maternal infection, we asked if the offspring of pregnant mice given a mid-gestation respiratory infection have cerebellar pathology resembling that seen in these disorders. We also tested the effects of maternal immune activation in the absence of virus by injection of the synthetic dsRNA, poly(I:C). We infected pregnant mice with influenza on embryonic day 9.5 (E9.5), or injected poly(I:C) i.p. on E12.5, and assessed the linear density of PCs in the cerebellum of adult or postnatal day 11 (P11) offspring. To study granule cell migration, we also injected BrdU on P11. Adult offspring of influenza- or poly(I:C)-exposed mice display a localized deficit in PCs in lobule VII of the cerebellum, as do P11 offspring. Coincident with this are heterotopic PCs, as well as delayed migration of granule cells in lobules VI and VII. The cerebellar pathology observed in the offspring of influenza- or poly(I:C)-exposed mice is strikingly similar to that observed in autism. The poly(I:C) findings indicate that deficits are likely caused by the activation of the maternal immune system. Finally, our data suggest that cerebellar abnormalities occur during embryonic development, and may be an early deficit in autism and schizophrenia.

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Additional Information:Copyright © 2009 Elsevier. Received 28 April 2008; revised 19 July 2008; accepted 29 July 2008. Available online 9 August 2008. We thank L. Chahal, K. Christenson and A. Mihalas for help with the experiments, B. Deverman and J. Jankowsky for useful comments on the paper, and D. McDowell and K. Hamilton for administrative support. This work was supported by gifts from Ginger and Ted Jenkins and Ruben Mettler, a McKnight Foundation Neuroscience of Brain Disorder Award, and grants from the Cure Autism Now Foundation, the National Institute of Mental Health (RO1 MH067978), and the Stanley Medical Research Institute.
Funding AgencyGrant Number
Ginger and Ted JenkinsUNSPECIFIED
McKnight FoundationUNSPECIFIED
Cure Autism Now FoundationUNSPECIFIED
National Institute of Mental Health (NIMH)RO1 MH067978
Stanley Medical Research InstituteUNSPECIFIED
Subject Keywords:Autism; Schizophrenia; Influenza; Cerebellum; Purkinje cell; Poly(I:C)
Issue or Number:1
PubMed Central ID:PMC2614890
Record Number:CaltechAUTHORS:SHIbbi09
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:12942
Deposited By: Archive Administrator
Deposited On:11 Jan 2009 06:29
Last Modified:08 Nov 2021 22:34

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