Lasting and Sex-Dependent Impact of Maternal Immune Activation on Molecular Pathways of the Amygdala.

Marissa R Keever,Alvaro G Hernandez,Courtni R Bolt,Sandra L Rodriguez-Zas,Pan Zhang,Bruce R Southey,Megan P Caputo,Laurie A Rund,Haley E Rymut,Rodney W Johnson,Alexandra K Houser,Adrienne M Antonson

doi:10.3389/fnins.2020.00774

Marissa R Keever, Alvaro G Hernandez + Show 10 more

Open Access

https://doi.org/10.3389/fnins.2020.00774

Copy DOI

Abstract

The prolonged and sex-dependent impact of maternal immune activation (MIA) during gestation on the molecular pathways of the amygdala, a brain region that influences social, emotional, and other behaviors, is only partially understood. To address this gap, we investigated the effects of viral-elicited MIA during gestation on the amygdala transcriptome of pigs, a species of high molecular and developmental homology to humans. Gene expression levels were measured using RNA-Seq on the amygdala for 3-week-old female and male offspring from MIA and control groups. Among the 403 genes that exhibited significant MIA effect, a prevalence of differentially expressed genes annotated to the neuroactive ligand–receptor pathway, glutamatergic functions, neuropeptide systems, and cilium morphogenesis were uncovered. Genes in these categories included corticotropin-releasing hormone receptor 2, glutamate metabotropic receptor 4, glycoprotein hormones, alpha polypeptide, parathyroid hormone 1 receptor, vasointestinal peptide receptor 2, neurotensin, proenkephalin, and gastrin-releasing peptide. These categories and genes have been associated with the MIA-related human neurodevelopmental disorders, including schizophrenia and autism spectrum disorders. Gene network reconstruction highlighted differential vulnerability to MIA effects between sexes. Our results advance the understanding necessary for the development of multifactorial therapies targeting immune modulation and neurochemical dysfunction that can ameliorate the effects of MIA on offspring behavior later in life.

Highlights

The maternal immune response triggered by pathogens and other environmental stressors during gestation can elicit an indirect response by the fetal immune cells (Kroismayr et al, 2004; Odorizzi and Feeney, 2016; Prins et al, 2018)
The differences between MPA and CON gilts in rectal temperatures and daily diet consumption indicated the activation of the maternal immune system in response to porcine reproductive and respiratory syndrome virus (PRRSV)
The number of reads was consistent across maternal immune activation (MIA) and sex groups, and the effects of MIA, sex, and MIA-by-sex interaction were tested on 16,175 genes that surpassed the minimum number of reads per MIA– sex combination

Summary

Introduction

The maternal immune response triggered by pathogens and other environmental stressors during gestation can elicit an indirect response by the fetal immune cells (Kroismayr et al, 2004; Odorizzi and Feeney, 2016; Prins et al, 2018). The relationship between MIA and neurodevelopmental disorders, including schizophrenia spectrum disorders (SSD) and autism spectrum disorders (ASD), and neurodegenerative disorders, such as Alzheimer’s disease (AD), in offspring has been established (Knuesel et al, 2014; Canetta et al, 2016; Mattei et al, 2017). These diseases share some behavior symptoms, comorbidities such as eating disorders, and genetic and environmental (i.e., MIA) agents (Canitano and Pallagrosi, 2017). The previous neurological disorders have been associated with abnormal structure and dysregulation of the amygdala (Schumann et al, 2011; Fernandez-Irigoyen et al, 2014) and share genes and molecular mechanisms including histocompatibility complex (MHC) genes (Anders and Kinney, 2015), glutamatergic and GABAergic-associated genes (Bourgeron, 2009; Marin, 2012; Li et al, 2016), and mitochondrial activity processes (Pieczenik and Neustadt, 2007; Sragovich et al, 2017)

Objectives

Methods

Results

Discussion

Conclusion