The long-term consequences of maternal LPS exposure

LPS, lipopolysaccharide, or better lipopolysaccharides are a group of large molecules consisting of a lipid attached to a polysaccharide. They are found on the outer cell membrane of Gram-negative bacteria and act as an endotoxin. It binds to the CD14/TLR4/MD2 receptor complex that can be found on the membrane of several immune cells (monocytes, dendritic cells, macrophages and B cells). Like PolyI:C, prenatal LPS, while not crossing the blood placental barrier, activates the maternal immune system which ultimately affect the foetus.

We currently have two projects aimed at investigating the long-term consequences of prenatal LPS treatment. In the first project, we specifically investigate how the timing of the maternal immune activation affects behaviour. Specifically, we have exposed pregnant rats to two consecutive injections of LPS on gestational days 10 and 11, 15 and 16 or 18 and 19. We have found that exposure on gestational days 10 and 11 (but not 15/16 or 18/19) leads to cognitive deficits in, among others, working memory capacity and selective attention. Additionally, we found that exposure of gestational days 15 and 16 (but not 10/11 and 18/19) leads to emotional deficits in, among others, reward sensitivity anticipatory pleasure and social interaction.

In the second project, we investigate the epigenetic changes induced by LPS. Specifically, we aim to perform both a targeted and a genome wide methylation approach. DNA methylation involves the addition of a methyl group on specific DNA nucleotides, typically (though not exclusively) cytosines. In most situations, DNA methylation leads to transcriptional repression, and thus to a reduction in protein production. By investigating different brain regions after LPS administration on gestational days 10 and 11 or 15 and 16, we hope to gain more insight into the neurobiological basis of the cognitive and emotional deficits induced by prenatal LPS.

This research is in part sponsored by a grant from the Neurological Foundation.

The long-term consequences of maternal polyI:C exposure

Polyinosinic:polycytidylic acid (PolyI:C) is an immunostimulant that simulates viral infections. Like viruses, it does not see to cross the blood placental barrier but activates the maternal immune system by stimulating the TLR3 receptor (which is found on several immune cells, such as B-cells, macrophages and dendritic cells). Components of the maternal immune system, such as interleukin-6 and others are known to cross the blood placental barrier to reach the foetal brain. Interleukins are known to activate microglia (the brain’s immune system) and during development can cause, what is known as a cytokine storm. This is then thought to subsequently alter the connectivity between different brain regions as well as neurotransmitter functioning, such as serotonin.

We currently have two different projects investigating the long-term consequences of polyI:C, one focussing on behaviour, one on the neurobiological changes in the brain.

In the behavioural project, we are investigating whether polyI:C exposure on gestational day 15 leads to changes in social behaviour throughout the lifetime of the rat. Specifically, we study changes in maternal separation induced ultrasonic vocalizations, social approach avoidance and empathy, using a helping behaviour paradigm in which rats can help a trapped rat escape. In addition, we will investigate whether environmental enrichment from very early on reverses some of these behavioural deficits.

After the behavioural experiments, the brains of the animals exposed to polyi:C and/or environmental enrichment will be investigated. In this project, we will be using a variety of standard immunohistochemical and molecular techniques and will focus predominantly on oligodendrocytes and synaptic connectivity. Oligodendrocytes are the glial cells that are principally involved in forming the myelin sheet around axons of nerve cells and there is some clinical evidence suggesting that the myelination is altered in for instance schizophrenia and autism spectrum disorder. Likewise, both disorders have been associated with altered synaptic connectivity, although interestingly in opposite directions. Thus, while research has found an increased spine density in autism spectrum disorder, a decrease has been reported in schizophrenia. Given that prenatal polyI:C has been used as a model for both disorders, it will be interesting to see how it affects spine density in rats.