Late prenatal immune activation causes hippocampal deficits in the absence of persistent inflammation across aging

Abstract

BackgroundPrenatal exposure to infection and/or inflammation is increasingly recognized to play an important role in neurodevelopmental brain disorders. It has recently been postulated that prenatal immune activation, especially when occurring during late gestational stages, may also induce pathological brain aging via sustained effects on systemic and central inflammation. Here, we tested this hypothesis using an established mouse model of exposure to viral-like immune activation in late pregnancy.MethodsPregnant C57BL6/J mice on gestation day 17 were treated with the viral mimetic polyriboinosinic-polyribocytidilic acid (poly(I:C)) or control vehicle solution. The resulting offspring were first tested using cognitive and behavioral paradigms known to be sensitive to hippocampal damage, after which they were assigned to quantitative analyses of inflammatory cytokines, microglia density and morphology, astrocyte density, presynaptic markers, and neurotrophin expression in the hippocampus throughout aging (1, 5, and 22 months of age).ResultsMaternal poly(I:C) treatment led to a robust increase in inflammatory cytokine levels in late gestation but did not cause persistent systemic or hippocampal inflammation in the offspring. The late prenatal manipulation also failed to cause long-term changes in microglia density, morphology, or activation, and did not induce signs of astrogliosis in pubescent, adult, or aged offspring. Despite the lack of persistent inflammatory or glial anomalies, offspring of poly(I:C)-exposed mothers showed marked and partly age-dependent deficits in hippocampus-regulated cognitive functions as well as impaired hippocampal synaptophysin and brain-derived neurotrophic factor (BDNF) expression.ConclusionsLate prenatal exposure to viral-like immune activation in mice causes hippocampus-related cognitive and synaptic deficits in the absence of chronic inflammation across aging. These findings do not support the hypothesis that this form of prenatal immune activation may induce pathological brain aging via sustained effects on systemic and central inflammation. We further conclude that poly(I:C)-based prenatal immune activation models are reliable in their effectiveness to induce (hippocampal) neuropathology across aging, but they appear unsuited for studying the role of chronic systemic or central inflammation in brain aging.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0437-y) contains supplementary material, which is available to authorized users.

Altered Hippocampal Gene Expression and Morphology in Fetal Piglets following Maternal Respiratory Viral Infection

“…In our model, an indication of excessive neural progenitor cell phagocytosis was evident in the decreased estimated hippocampal neuronal cell density in MIA piglets, while microglial overactivation (measured by MHCII expression) was not apparent. A lack of microglial activation aligns with previous studies [30, 79-81], though we acknowledge that lasting microglial activation in this model cannot be ruled out solely by MHCII expression. Though MHCII is a widely used marker of classic microglial activation, microglia continuously take on varying states of activation that do not necessarily fall into classic or alternative categorizations [82-84] and resting or quiescent microglia still actively survey their environment and can engulf and clear parenchymal debris [85].…”

“…Indeed, Wu et al [14] and Mouihate and Mehdawi [15] demonstrated an increased expression of IL-6, STAT3, and pSTAT3 in the fetal brain in the immediate hours following MIA, though these studies did not extend past 24 h after MIA induction. In fact, the most compelling and comprehensive evidence of the impact of MIA on fetal brain gene and protein expression to date has focused on the immediate time points following immune activation [19, 90], and several studies support the idea that neuroinflammation is resolved by the neonatal and postnatal periods [79, 81, 91]. …”

Environment matters: microglia function and dysfunction in a changing world

“…Specifically, microglia collected at P28 from piglets infected with virus at P7, display enhanced phagocytic and migratory activity, increased sensitivity to a second challenge with LPS and Poly I:C, as well as increased soma size compared to controls, closely supporting our findings in rodents [20,44]. Conversely, a few prenatal infection models have failed to demonstrate overt microglial activation in the offspring [45,46]. Timing – and resulting alterations in developmental trajectory - are undoubtedly key (see [23] in this issue).…”

Intake of 7,8-Dihydroxyflavone During Juvenile and Adolescent Stages Prevents Onset of Psychosis in Adult Offspring After Maternal Immune Activation

“…Furthermore, the reduction of expression of BDNF and TrkB receptor has been found in the prefrontal cortex and hippocampus of patients with schizophrenia2526. The deficits in hippocampal BDNF expression are also found in placentas and offspring after maternal poly(I:C) exposure during pregnancy in rodents1227. These findings all suggest that decreased BDNF-TrkB signaling plays a role in the pathophysiology of schizophrenia.…”

“…Maternal immune activation (MIA) in rodents has a great impact on brain development and behavioral abnormalities in their offspring3121314. The offspring of prenatal rodents exposed to polyriboinosinic-polyribocytidylic acid [poly(I:C)] mimics schizophrenia-like behavioral abnormalities in adulthood1415.…”