Maternal Immune Activation Produces Cerebellar Hyperplasia and Alterations in Motor and Social Behaviors in Male and Female Mice

Abstract

There have been suggestions that maternal immune activation is associated with alterations in motor behavior in offspring. To explore this further, we treated pregnant mice with polyinosinic:polycytidylic acid (poly(I:C)), a viral mimetic that activates the innate immune system, or saline on embryonic days 13-15. At postnatal day (P) 18, offspring cerebella were collected from perfused brains and immunostained as whole-mounts for zebrin II. Measurements of zebrin II+/- stripes in both sexes indicated that prenatal poly(I:C)-exposed offspring had significantly wider stripes; this difference was also seen in similarly treated offspring in adulthood (~P120). When sagittal sections of the cerebellum were immunostained for calbindin and Purkinje cell numbers were counted, we observed greater numbers of Purkinje cells in poly(I:C) offspring at both P18 and ~ P120. In adolescence (~P40), both male and female prenatal poly(I:C)-exposed offspring exhibited poorer performance on the rotarod and ladder rung tests; deficits in performance on the latter test persisted into adulthood. Offspring of both sexes from poly(I:C) dams also exhibited impaired social interaction in adolescence, but this difference was no longer apparent in adulthood. Our results suggest that maternal immune exposure at a critical time of cerebellum development can enhance neuronal survival or impair normal programmed cell death of Purkinje cells, with lasting consequences on cerebellar morphology and a variety of motor and non-motor behaviors.

Maternal immune activation in neurodevelopmental disorders

“…A reduction in Purkinje cell number was detected after induction of MIA with influenza virus or Poly(I:C) at GD9.5 in mice (Shi et al, 2009) and with Escherichia coli injections in rats (GD17) (Wallace et al, 2010), similar to the cerebellar Purkinje cell defects observed in postmortem samples of patients with ASD . In contrast, MIA induction in mid-gestation (GD13-15) with Poly(I:C) results in an increase in Purkinje cell numbers in juvenile and adult mice (Aavani et al, 2015). This may represent a narrow window in which inflammatory cytokines enhance proliferation or inhibit apoptosis of Purkinje cell precursors.…”

Maternal Immune Activation and Autism Spectrum Disorder: From Rodents to Nonhuman and Human Primates

“…Later assessments of social behavior in MIA mouse offspring have relied heavily upon on simplistic, automated tools, such as the three-chamber social approach test to quantify sociability as indexed by a preference for a social versus a nonsocial stimulus (64). Several laboratories have now reported that mice exposed to PolyIC challenge during gestation fail to demonstrate species typical preferences for the social stimulus when evaluated in adolescence or adulthood (60, 62, 63, 65-72), though deficits may be strain specific (61). Only a small number of studies have evaluated the effects of MIA on complex, reciprocal social interactions.…”

Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

“…Besides post--pubertal synaptic deficits, the delayed onset of prenatal poly(I:C)--induced deficits in PPI may also involve altered functional maturation of the subcortical dopamine system Vuillermot et al, 2010), brain volumetric changes throughout adolescence (Piontkewitz et al, 2011), and altered maturation of prefrontal GABAergic systems (Richetto et al, 2014). It should also be noted that prenatal poly(I:C)--induced immune activation can lead to various behavioral and neuronal abnormalities with early juvenile or adolescent onsets, including hypersensitivity to dopamine--stimulating psychotomimetic drugs (Meyer et al, 2008,;Vuillermot et al, 2010), cognitive deficits , impairments in social interaction (Aavani et al, 2015), and deficits in hippocampal neurogenesis . Hence, whereas the present findings may be more important for neuropsychiatric disorders with adult onsets, prenatal immune activation models are generally also relevant for neurodevelopmental disorders that are characterized by overt symptomatology in childhood or early adolescence.…”