Maternal immune activation results in complex microglial transcriptome signature in the adult offspring that is reversed by minocycline treatment

Daniele Mattei ,Erik Boddeke ,Bart J L Eggen ,Alice Buonfiglioli ,W Schaafsma ,Tobias L Roß ,Philipp Jordan ,Bożena Kamińska ,Peter Brust ,Andranik Ivanov ,Ana Pombo ,Dilansu Güneykaya ,Winnie Deuther‐Conrad ,Osama Sabri ,Dieter Beule ,Swen Hesse ,Marianne Patt ,Carmelo Ferrai ,Helmut Kettenmann ,Piotr Przanowski ,Susanne Wolf

doi:10.1038/tp.2017.80

Abstract

Maternal immune activation (MIA) during pregnancy has been linked to an increased risk of developing psychiatric pathologies in later life. This link may be bridged by a defective microglial phenotype in the offspring induced by MIA, as microglia have key roles in the development and maintenance of neuronal signaling in the central nervous system. The beneficial effects of the immunomodulatory treatment with minocycline on schizophrenic patients are consistent with this hypothesis. Using the MIA mouse model, we found an altered microglial transcriptome and phagocytic function in the adult offspring accompanied by behavioral abnormalities. The changes in microglial phagocytosis on a functional and transcriptional level were similar to those observed in a mouse model of Alzheimer’s disease hinting to a related microglial phenotype in neurodegenerative and psychiatric disorders. Minocycline treatment of adult MIA offspring reverted completely the transcriptional, functional and behavioral deficits, highlighting the potential benefits of therapeutic targeting of microglia in psychiatric disorders.

Highlights

In recent years, microglia as the brain’s intrinsic immune cells have emerged as having new roles in the pathophysiology of psychiatric disorders such as schizophrenia.[1]
In the first set of experiments, we explored the effect of a chronic minocycline treatment on mouse behavioral traits similar to positive, negative and cognitive symptoms displayed by human schizophrenic patients
We found a significant enrichment in genes associated with phagocytosis that confirms impairment of this particular function in both animal models; similar results were obtained in the functional phagocytosis assay (Supplementary Table 2b)

Summary

Introduction

Microglia as the brain’s intrinsic immune cells have emerged as having new roles in the pathophysiology of psychiatric disorders such as schizophrenia.[1]. Epidemiological studies have linked prenatal influenza infections with an increased risk of developing schizophrenia in the offspring.[12,13] Injection of the viral mimic polyinosinic:polycytidilic acid (Poly(I:C)) to pregnant rodent dams has been shown to induce a series of behavioral, morphological, cytoarchitectural and biochemical changes in the brain of adult offspring, which are highly comparable to the abnormalities observed in human schizophrenic patients.[14,15] The maternal immune activation (MIA) in humans and animal models alike could impact on the fetal microglia and result in functional changes that are retained in adulthood

Methods

Results

Conclusion