Infections during pregnancy may interfere with key genes associated with autism and prenatal brain development

cjb250 — Tue, 21 Mar 2017 09:00:29 +0000

In a study published today in the journal Molecular Psychiatry, researchers at the ̽��ֱ�� of Cyprus, ̽��ֱ�� of Cambridge, ̽��ֱ�� of California, San Diego, and Stanford ̽��ֱ�� used rats and mice to help map the complex biological cascade caused by the mother’s immune response, which may lead to important consequences.

Maternal infections during pregnancy are a known risk factor for abnormal fetal development. Most strikingly, this has been seen during the recent emergence of Zika virus, which led to babies being born with an abnormally small head and brain (known as ‘microcephaly’). In the case of Zika, the virus has its impact by directly attacking fetal brain tissue. However, for most other infections, such as influenza, the infectious agent typically has a more indirect impact on fetal development.

Large population-based studies have previously shown that a variety of maternal infections during pregnancy are associated with small increases in the risk for psychiatric disorders, including autism spectrum disorders and schizophrenia. Other studies have shown that this effect is due not to the infectious agents themselves, but simply due to triggering a strong immune response in a pregnant mother – a phenomenon known as ‘maternal immune activation’.

“It’s important to underscore that the increase in risk is really small – too small to be meaningfully applied to specific individuals, and is only seen in very large studies when examining many thousands of people,” says Dr Michael Lombardo, lead author of the work from the ̽��ֱ�� of Cyprus and the ̽��ֱ�� of Cambridge. “Nevertheless, the biological cascade triggered by this effect is not well understood, particularly in how it may be similar to known biology behind conditions like autism. This was the motivation behind why we did the study.”

To understand how activating a mother’s immune system may affect her child’s brain development, Dr Lombardo and colleagues examined the activity of genes in the brain after injecting pregnant rats and mice with a substance called lipopolysaccharide. This substance contains no infectious agent and thus does not make the mothers sick, but will elicit a strong immune response in the mother, characterized by an increase in levels of cytokines. These are small immune signalling molecules that can have important effects on brain cells and the connections between these cells (known as ‘synapses’ in the fetus’s brain.

̽��ֱ��scientists found that maternal immune activation alters the activity of multiple genes and pathways in the fetus’s brain. Importantly, many of these genes are known to be important in the development of autism and to key brain developmental processes that occur before birth. They believe that these effects may help to explain why maternal immune activation carries a small increased risk for later atypical neurodevelopment.

“ ̽��ֱ��more we understand about how brain development is disrupted by these effects, the higher the chance of finding amenable targets for potential therapeutic intervention or for informing how to prevent such risk from occurring in the first place,” says Dr Tiziano Pramparo, senior author on the work from the ̽��ֱ�� of California, San Diego.

While the effects caused by maternal immune activation are transient, the researchers argue that they may be very potent during fetal development and may cause different characteristics in the individual depending on when it occurs during pregnancy. ̽��ֱ��work underscores the importance of the idea that genes and the environment interact and that their interaction may have important roles in better understanding how risk for neurodevelopmental disorders manifests.

̽��ֱ��research was funded in part by the ̽��ֱ�� of California San Diego Altman Clinical and Translational Research Institute, the National Institutes of Health, the Simons Foundation Autism Research Initiative and the Child Health Research Institute at Stanford ̽��ֱ��.

Reference
Lombardo, MV et al. Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder. Molecular Psychiatry; 21 March 2017; DOI: 10.1038/mp.2017.15

If a mother picks up an infection during pregnancy, her immune system will kick into action to clear the infection – but this self-defence mechanism may also have a small influence how her child’s brain develops in the womb, in ways that are similar to how the brain develops in autism spectrum disorders. Now, an international team of researchers has shown why this may be the case, in a study using rodents to model infection during pregnancy.

It’s important to underscore that the increase in risk is really small.. Nevertheless, the biological cascade triggered by this effect is not well understood, particularly in how it may be similar to known biology behind conditions like autism

Michael Lombardo

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Autism affects different parts of the brain in women and men

gm349 — Fri, 09 Aug 2013 08:27:04 +0000

Autism affects different parts of the brain in females with autism than males with autism, a new study reveals. ̽��ֱ��research is published today in the journal Brain as an open-access article.

Scientists at the Autism Research Centre at the ̽��ֱ�� of Cambridge used magnetic resonance imaging to examine whether autism affects the brain of males and females in a similar or different way. They found that the anatomy of the brain of someone with autism substantially depends on whether an individual is male or female, with brain areas that were atypical in adult females with autism being similar to areas that differ between typically developing males and females. This was not seen in men with autism.

“One of our new findings is that females with autism show neuroanatomical ‘masculinization’,” said Professor Simon Baron-Cohen, senior author of the paper. “This may implicate physiological mechanisms that drive sexual dimorphism, such as prenatal sex hormones and sex-linked genetic mechanisms.”

Autism affects 1% of the general population and is more prevalent in males. Most studies have therefore focused on male-dominant samples. As a result, our understanding of the neurobiology of autism is male-biased.

“This is one of the largest brain imaging studies of sex/gender differences yet conducted in autism. Females with autism have long been under-recognized and probably misunderstood,” said Dr Meng-Chuan Lai, who led the research project. “ ̽��ֱ��findings suggest that we should not blindly assume that everything found in males with autism applies to females. This is an important example of the diversity within the ‘spectrum’.”

Dr Michael Lombardo, who co-led the study, added that although autism manifests itself in many different ways, grouping by gender may help provide a better understanding of this condition.

He said: “Autism as a whole is complex and vastly diverse, or heterogeneous, and this new study indicates that there are ways to subgroup the autism spectrum, such as whether an individual is male or female. Reducing heterogeneity via subgrouping will allow research to make significant progress towards understanding the mechanisms that cause autism.”

If you are a journalist and would like more information about this story, please contact: Genevieve Maul, Office of Communications, ̽��ֱ�� of Cambridge. Email: Genevieve.Maul@admin.cam.ac.uk; Tel: 01223 765542.

New research sheds light on previously under-researched area of study – females with autism.

̽��ֱ��findings suggest that we should not blindly assume that everything found in males with autism applies to females.

Dr Meng-Chuan Lai

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̽��ֱ�� of Cambridge - Michael Lombardo

Infections during pregnancy may interfere with key genes associated with autism and prenatal brain development

Autism affects different parts of the brain in women and men