Maternal infections during pregnancy can affect neural development of offspring

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The mother’s health is very important for the fetus’s brain development during pregnancy. Many factors play key roles for healthy brain development, including nutrition, stress, hormonal balance and the mother’s immune system.

It has been observed in both humans and animals that severe infections in the pregnant mother are a risk factor for developing psychiatric disorders such as schizophrenia and autism spectrum disorders later in life for the offspring.

Now, researchers from Copenhagen have shown in mice how infections in the mother can cause the stem and precursor cells to neuronal cells in the brain to have their development impaired. The new study is published in the scientific journal Molecular Psychiatry.

“The connection has been made in animal studies and clinical observation studies. However, this is the first time that we show how infections during pregnancy affect brain development and can lead to cognitive impairment.

While many factors have been hypothesised or indicated, it is important that we show the steps of neuronal development that are actually affected,” says Konstantin Khodosevich, Associate Professor in the Biotech Research and Innovation Centre (BRIC).

Immediate and long-lasting effect

The researchers studied the development of neurons in mice.

The mother’s immune response to infection had an effect stretching from stem cells and precursor cells to neuronal cells leading to profound disruption in their development in the brain. More specifically, the development of cortical GABAergic interneurons – the key neuronal class that provides inhibition in the brain – was impaired.

The effect was immediate and cascaded to dramatic long-lasting impairments, thus resulting in multiple “hits” during the process of neuronal development – from the time neurons are born to the time they mature.

Furthermore, the researchers also concluded that the newborn mice showed symptoms resembling those from human psychiatric disorders including decreased prepulse inhibition, altered social interactions and cognitive decline.

It has been observed in both humans and animals that severe infections in the pregnant mother are a risk factor for developing psychiatric disorders such as schizophrenia and autism spectrum disorders later in life for the offspring.

“There are big technological and ethical issues about studying this in humans because of the vulnerability of pregnant women.

That is why we study how the mechanisms work in mice. Psychiatric disorders are really complex and for some of them, we are still only guessing how they arise. We really want to contribute to the scientific understanding of these diseases,” says Konstantin Khodosevich.

Deep-dive into molecular mechanisms

One of the major findings of the study was showing the effects of having the infections at different times during the pregnancy.

Depending on the time of infection, different precursor cells, and as a result different neurons, were affected.

This means that the timing of infection is very important and can lead to varying outcomes based on which stage of brain development is affected. This can potentially underlie the complexity of psychiatric disorders.

The researchers are now looking forward to dive deeper into the molecular mechanisms and signaling pathways behind the impairment of the interneuron development.


In utero environment critically affects the brain development, thereby modifying neurobehavior of the offspring after birth (Rees and Harding, 2004).

Substances that are ingested by a pregnant woman can cross the placenta and adversely affect fetal development.

Some are unavoidable medications due to the mother’s medical condition, such as epilepsy or depression, but others are consumed by an expectant mother unbeknown to the risks and effects. In some cases, an excessive amount may be taken by a pregnant woman due to the addiction.

During brain development, newly generated neurons undergo morphological changes followed by migrating from the germinal layer through the intricate network of extracellular matrix to establish connections with other cells in a highly ordered fashion (Rakic, 19721995Metin et al., 2008).

Two major modes of migration in the cerebral cortex are known (Copp and Harding, 1999Guerrini and Parrini, 2010). The first is radial migration. Excitatory neurons generated in the proliferative zones of the dorsal telencephalic primordium radially migrate toward the pial surface of the cerebral cortex along the radial axis.

These neurons use the cellular processes that are elongated from the radial glial cells, which are ascending neural progenitor cells (NPCs), as the scaffold of their migration (Rakic, 1972Ayala et al., 2007Figure 1).

Once arriving at the superficial layer, the neurons detach from the radial glial processes to settle down in the cortical plate. Another mode of neuronal migration, known as tangential migration, is employed by inhibitory interneurons.

Those neurons migrate tangentially from the ganglionic eminences (GE) to the cerebral cortex (Marín and Rubenstein, 2001Ayala et al., 2007Figure 1).

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FIGURE 1
Modes of neuronal migration in cortical development. The schematic diagram illustrates two major modes of migration. Excitatory neurons migrate radially from ventricular surface toward the pial surface of the neocortex using radial glial cells as their scaffolds whereas the inhibitory neurons migrate tangentially from the ganglionic eminences to the neocortex.

Any disturbances of these two modes of migration cause neuronal migration disorders (NMDs), and the consequent malformations are detectable by brain imaging in NMD patients (Roberts, 2018). Profound cases of NMDs include lissencephaly, heterotopia, and focal dysplasia (Guerrini and Parrini, 2010Roberts, 2018).

Precise control of the migration and positioning of both excitatory and inhibitory neurons are particularly important for the formation of synaptic excitation and inhibition (E/I) balanced circuit in the brain. Therefore the E/I imbalance is the main cause of epilepsy in NMD patients (Copp and Harding, 1999). Other neurodevelopmental and psychiatric disorders, including autism spectrum disorders (ASD), and schizophrenia are also associated with NMDs (Canitano and Pallagrosi, 2017).

In addition to the genetic causes, harmful prenatal environment also leads to neuronal migration defects (Metin et al., 2008). When developmental neurotoxicology first emerged, various paradigms of exposure were deployed in many species to recapitulate human pathophysiology, including defects of neuronal migration.

Decades later, many recent studies have utilized genetic tools and cutting edge molecular techniques in those preclinical animal models to decipher the underlying mechanisms of neuronal migration defects under the stress exposure. In this review, we summarize such recent findings in animal research and discuss the mechanisms shared by various types of environmental stress as the targets of interventions.


Source:
University of Copenhagen
Media Contacts:
Konstantin Khodosevich – University of Copenhagen
Image Source:
The image is in the public domain.

Original Research: Closed access
“Maternal inflammation has a profound effect on cortical interneuron development in a stage and subtype-specific manner”. Navneet A. Vasistha, Maria Pardo-Navarro, Janina Gasthaus, Dilys Weijers, Michaela K. Müller, Diego García-González, Susmita Malwade, Irina Korshunova, Ulrich Pfisterer, Jakob von Engelhardt, Karin S. Hougaard & Konstantin Khodosevich.
Molecular Psychiatry doi:10.1038/s41380-019-0539-5.

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