Maternal Immune Activation Causes Behavioral Impairments and Altered Cerebellar Cytokine and Synaptic Protein Expression

Abstract

Emerging epidemiology studies indicate that maternal immune activation (MIA) resulting from inflammatory stimuli such as viral or bacterial infections during pregnancy serves as a risk factor for multiple neurodevelopmental disorders including autism spectrum disorders and schizophrenia. Although alterations in the cortex and hippocampus of MIA offspring have been described, less evidence exists on the impact on the cerebellum. Here, we report altered expression of cytokines and chemokines in the cerebellum of MIA offspring, including increase in the neuroinflammatory cytokine TNFα and its receptor TNFR1. We also report reduced expression of the synaptic organizing proteins cerebellin-1 and GluRδ2. These synaptic protein alterations are associated with a deficit in the ability of cerebellar neurons to form synapses and an increased number of dendritic spines that are not in contact with a presynaptic terminal. These impairments are likely contributing to the behavioral deficits in the MIA exposed offspring.

Maternal Exposures Associated with Autism Spectrum Disorder in Jamaican Children

“…Recent literature has provided evidence that MIA induces upregulation of the expression of proinflammatory cytokines, including IL-17a, which caused abnormal cortical development (Choi et al, 2016), and TNFα, which altered synaptic development in the cerebellum of exposed offspring (Pendyala et al, 2017). Upregulated expression of both IL-17a and TNFα also resulted in autism-like behaviors and deficits in social interaction in MIA-exposed offspring (Choi et al, 2016; Pendyala et al, 2017). Furthermore, upregulated expression of IL-17a and its receptor in the fetal brain may have led to the formation of cortical patches associated with MIA-induced behavioral abnormalities, though the exact mechanism is still unknown (Shin et al, 2017).…”

Methimazole Inhibits the Expression of GFAP and the Migration of Astrocyte in Scratched Wound Model In Vitro

“…Our results were consistent with these previous results. Moreover, neuroinflammation and cytokines could greatly impact the neuronal function via adversely regulating the synaptic plasticity or synaptic protein function [28,29]. Therefore, the fact that methimazole could directly block the release of these cytokines after CNS injury could protect neurons from the "secondary attack" of the subsequent inflammatory response.…”

Role of short-chain fatty acids in the gut-brain axis in schizophrenia: contribution to immune activation and pathophysiology in humans and mice

“…Experiments 1 and 2 investigated the impacts of excessive SCFA intake in peri-puberty or adulthood on the expression of schizophrenia-relevant behaviors and immune activation in normal mice. Experiment 3 explored the impacts of SCFA elevation on the expression of schizophrenia-relevant behaviors in adulthood and immune activation in a mouse model of schizophrenia: maternal immune activation (MIA)[42]. The potential roles of inflammation pathways in the effects of SCFAs on mice were evaluated by feeding the anti-inflammatory drug minocycline concurrently with SCFAs.…”

“…In experiment 3, mice prenatally exposed to immune stimulation or sodium-matched water were treated with combined SCFAs and minocycline, SCFAs alone, minocycline alone, or saline during PD 57 - 84 and underwent behavioral testing one week later. MIA was established as published previously[42]. Dosage of agents and behavioral tests were identical in all three experiments.…”