title: Activation of the maternal immune system alters cerebellar development in the offspring.
abstract: 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.
authors.affiliation: Biology Division, California Institute of Technology, 391 S. Holliston Avenue, M/C 216-76 Pasadena, CA 91125, USA.
authors.forename: Limin
authors.initials: L
authors.lastname: Shi
authors.forename: Stephen E P
authors.initials: SE
authors.lastname: Smith
authors.forename: Natalia
authors.initials: N
authors.lastname: Malkova
authors.forename: Doris
authors.initials: D
authors.lastname: Tse
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Su
authors.forename: Paul H
authors.initials: PH
authors.lastname: Patterson