Activation of the maternal immune system alters cerebellar development in the offspring - PubMed (original) (raw)

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

Limin Shi et al. Brain Behav Immun. 2009 Jan.

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.

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Figures

Figure 1

Figure 1

Adult offspring of infected mothers display a PC deficit in lobule VII. Calbindin staining of adult cerebella from offspring of control (A, C) and infected mothers (B, D) reveals a deficit in lobule VII in the latter. Panels C and D (bar = 200 μm) are higher magnification views of panels A and B (bar =800 μm).

Figure 2

Figure 2

Young and adult offspring of infected mothers have a PC deficit specifically in lobule VII. (a) Quantification of PC linear density reveals a 33% deficit in lobule VII of the adult offspring of infected mothers, while no difference from controls is found in lobule V. (b) A similar, localized deficit is observed in the P11 offspring of infected mothers (* p < .01).

Figure 3

Figure 3

Heterotopic PCs are found in the offspring of infected mothers. Some P11 (A, bar = 200 μm) and adult (B, bar = 100 μm) offspring of infected mothers display large, calbindin+ cells (white arrowheads and arrow) in the white matter of lobules VI or VII. Such cells are rarely seen in other lobules, or in control cerebella.

Figure 4

Figure 4

Granule cell development is abnormal in the offspring of infected mothers. At P17, control mice lack an EGL (A, C), while a persistent EGL is observed in the offspring of infected mothers (B, D), particularly around lobules VI and VII (arrowhead). In the adult, Nissl staining reveals the normal absence of an EGL in both control (E) and experimental (F) offspring. Moreover, no GABAR α6 staining is found in the ML of the adult control (G) or experimental (H) offspring, indicating that the GCs have completed their migration into the IGL. Scale bars A, B = 200μm; C–H = 100μm.

Figure 5

Figure 5

Purkinje cell loss in the adult offspring of immune-activated mothers is localized to lobule VII. A single poly(I:C) injection in pregnant mice causes a deficit in PC density in the adult offspring, specifically in lobule VII. (* p < 0.02)

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