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Virus in pregnancy linked to austim disorders

Findings in mice may help explain how viral infection during pregnancy raises the risk for autism and schizophrenia in mouse pups — and humans.


Viral infection in mother mice, may be a key factor in the later appearance of certain neurodevelopmental disorders - known as disrupted fetal immune system development. The finding emerged from a Weizmann Institute study published in Science, June 23, 2016.


The study may explain how a mother's infection with the cytomegalovirus (CMV) in pregnancy, affects both her and her pups' immune systems, increasing the risk autism or schizophrenia might later develop in her pups' lives.


This increased risk for neurodevelopmental diseases was discovered many years ago in epidemiological studies and then confirmed in mouse models. The Weizmann study, led by Dr. Ido Amit and Prof. Michal Schwartz, in the Immunology and Neurobiology Departments, provides a possible explanation for this increase on the cellular and mechanical molecular levels.


"Previous studies had shown that the timing of the disruption in the mother's immune system during pregnancy affects the type of brain damage her child may develop.

"For example, a viral infection in early pregnancy raises the risk of autism, whereas an infection later in the pregnancy raises the risk of schizophrenia.


Ido Amit PhD, Assistant Professor, Immunology Department, Weizmann Institute of Science. Received the 2015 EMBO Gold Medal for work revealing function of immune system.


Orit Matcovitch-Natan, a graduate student in the laboratories of both Amit and Schwartz, studied the only immune cells present in the brain — the microglia that contribute to the brain's development and maintenance. They identified three distinct stages, parallel to those of the developing brain: (1) early cells that populate the brain of the embryo shortly after its inception, (2) pre-microglia and (3) adult cells.

Screening these cells, scientists were then able to define each of these stages in terms of the genes activated and functioning at that stage. This included epigenetic features such as the activation of histone proteins which "package" DNA and affect whether a gene is expressed or suppressed, i.e. the function of that gene in development. Scientists were also able to characterize the functions of some microglia genes.

The second, pre-microglia stage proved the most sensitive to disruption. Taking place close to birth and shortly thereafter, this stage is just when the developing brain undergoes a vital "pruning" of inappropriate neural synapses. Pre-microglia are important in removing superfluous neural networks, which shapes and strengthens connections among remaining neurons.

When the brains of pregnant mice are exposed to materials that mimic a CMV infection, development of their pups' pre-microglia are disrupted. Genes involved in maturation of those pre-microglia cells are expressed at the wrong time and proceed to an adult stage earlier than usual. The pups later exhibit abnormal behavior — with disturbed social interactions similar to schizophrenia.


"We've discovered that it's essential for the development of immune cells in the brain to be synchronized with the development of the brain itself.

"Premature shift of the microglia in mice to an adult stage leads to brain malfunction later."


Michal Schwartz PhD, Professor of Neuroimmunology, The Department of Neurobiology, The Weizmann Institute of Science.


The scientists believe disrupted coordination between development of microglia and the brain increases risk for disorders such as autism and schizophrenia in human beings as well as in mice. They observed that a heightened immune response to viral infection in the mother's body may be responsible for disrupting the timing of microglia development.

"Our research has paved the way for studying the effects of other viruses on the mother's immune system in general, and on her offspring's brain development in particular." adds Orit Matcovitch-Natan, post doctoral student, the Weizmann Institute of Science.


Weizmann scientists also established a connection between development of brain microglia and intestinal microbes — known as the microbiome.


Newborn mice born free from any microbes, had maturation delay of their microglia. This suggests that in human babies, factors that shape the microbiome — natural ones such as breastfeeding, or therapeutic ones such as antibiotics — may affect the immune cells in the baby's brain and consequently a baby's brain development.

A direct relationship of this work to human beings must still be proven, but improved understanding of brain development processes will assist in preventing neurological disorders in babies caused by disruptions in a mother's immune system.

Dr. Ido Amit's research is supported by the Benoziyo Endowment Fund for the Advancement of Science; David and Fela Shapell Family Foundation INCPM Fund for Preclinical Studies; Wolfson Family Charitable Trust; Leona M. and Harry B. Helmsley Charitable Trust; and Rosenwasser Fund for Biomedical Research. Dr. Amit is the incumbent of the Alan and Laraine Fischer Career Development Chair.

Prof. Michal Schwartz's research is supported by Sonia T. Marschak, Lincolinwood, IL; Elaine Petchek, Scarsdale, NY; Nathan and Dora Oks, France; and Hilda Namm, Larkspur, CA. Prof. Schwartz is the incumbent of the Maurice and Ilse Katz Professorial Chair of Neuroimmunology.

Taking part in the study were Dr. Deborah R. Winter, Amir Giladi, Eyal David and Dr. Hadas Keren-Shaul, as well as Dr. Eran Elinav and Christoph Thaiss of the Immunology Department, and Hila Ben-Yehuda, Merav Cohen and Dr. Kuti Baruch of the Neurobiology Department. Matcovitch-Natan and Amit Spinrad, also a graduate student, belonged to both departments. Study participants also included Prof. Michael H. Sieweke of Centre National de la Recherche Scientifique, France.

The Weizmann Institute of Science in Rehovot, Israel, is one of the world's top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to scientists, students, technicians and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials and developing new strategies for protecting the environment.


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Jul 13, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   



Microglia (bright green) in an adult mouse brain, viewed under a fluorescent microscope.
Image Credit: Weizmann Institute of Science, Israel.


 


 

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