Maternal Immune Activation and the Development of Dopaminergic Neurotransmission of the Offspring: Relevance for Schizophrenia and Other Psychoses

Abstract

Prenatal infections have been linked to the development of schizophrenia (SCZ) and other neurodevelopmental disorders in the offspring, and work in animal models indicates that this is to occur through the maternal inflammatory response triggered by infection. Several studies in animal models demonstrated that acute inflammatory episodes are sufficient to trigger brain alterations in the adult offspring, especially in the mesolimbic dopamine (DA) system, involved in the pathophysiology of SCZ and other disorders involving psychosis. In the current review, we synthesize the literature on the clinical studies implicating prenatal infectious events in the development of SCZ. Then, we summarize evidence from animal models of maternal immune activation (MIA) and the behavioral and molecular alterations relevant for the function of the DAergic system. Furthermore, we discuss the evidence supporting the involvement of maternal cytokines, such as interleukin 6 (IL-6) and leptin (a hormone with effects on inflammation) in mediating the effects of MIA on the fetal brain, leading to the long-lasting effects on the offspring. In particular, IL-6 has been involved in mediating the effects of MIA animal models in the offspring through actions on the placenta, induction of IL-17a, or triggering the decrease in non-heme iron (hypoferremia). Maternal infection is very likely interacting with additional genetic and environmental risk factors in the development of SCZ; systematically investigating how these interactions produce specific phenotypes is the next step in understanding the etiology of complex psychiatric disorders.

How do established developmental risk-factors for schizophrenia change the way the brain develops?

“…Maternal iron deficiency elevates placental inflammation 115 as well as corticosterone production in both the dam and newborn brain with corresponding alterations in GR expression in the developing hippocampus 116 . Maternal inflammation also frequently leads to acute iron deficiencies 117 . In addition, maternal protein deprivation is a well-known regulator of HPA function 113 .…”

ADHD: Reviewing the Causes and Evaluating Solutions

“…This does not imply a lack of importance of this variation, but rather highlights the variability in the genetic etiology of this condition. Moreover, while the dopaminergic system is highly involved in the pathophysiology of ADHD, given its role in CNS development, it is also strongly related with other neuropsychiatric conditions, such as autism [ 78 , 94 , 95 ] and schizophrenia [ 78 , 94 , 96 , 97 ].…”

Schizophrenia, the gut microbiota, and new opportunities from optogenetic manipulations of the gut-brain axis

“…Among the relevant causes inducing SCZ, prenatal and postnatal environmental vulnerabilities and the immunity system reactions are the most investigated. For example, maternal immune activation (MIA), which refers to a maternal immune system triggered by infectious or infectious‐like stimuli, has been recently considered as a “neurodevelopmental primer" acting during specific gestational timings and increasing the risk for SCZ in offspring [ 46 – 49 ]. Notably, a set of studies inferred that a cascade of cytokines and immunologic alterations are transmitted to the fetus, resulting in adverse phenotypes, most notably in the central nervous system [ 50 , for review].…”

“…Notably, a set of studies inferred that a cascade of cytokines and immunologic alterations are transmitted to the fetus, resulting in adverse phenotypes, most notably in the central nervous system [ 50 , for review]. In addition, these studies implied that maternal respiratory infections, influenza, Toxoplasma gondii infections, and others are possible biomarkers of MIA, and the inflammatory mediators released following all types of infections may be fundamentally involved in the etiology of SCZ in offspring [ 46 ]. The viral mimic polyinosinic–polycytidylic acid [Poly (I:C)] is used to create an animal model of MIA, and it is recently emerging as a highly potent preclinical research tool in the quest for both symptomatic and preventive treatment approaches [ 50 ].…”