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How Prenatal Maternal Infections May Affect Genetic Factors in Autism Spectrum Disorder

Summary: According to researchers, maternal immune activation during pregnancy can disrupt the expression of genes and processes associated with Autism.

Source: UCSD.

Researchers find activation of maternal immune system during pregnancy disrupts expression of key genes and processes associated with autism and prenatal brain development.

For some infections, such as Zika, the virus passes through the placenta and directly attacks the fetus. For others, such as the H1N1 influenza, the virus induces maternal immune activation (MIA) by triggering a woman’s immune system during pregnancy. Both Zika and MIA mechanisms may lead to potentially disastrous neurological repercussions for the unborn child, such as microcephaly (an undersized, underdeveloped brain and head) in the case of Zika or cortical abnormalities with excess numbers of neurons, patches of disorganized cortex, synapse mal-development and early brain overgrowth in some cases of MIA.

Large population-based studies suggest MIA caused by infection during pregnancy are also associated with small increases in risk for psychiatric disorders, including autism spectrum disorder (ASD). In a new study published today in Molecular Psychiatry, researchers at the University of California San Diego School of Medicine, University of Cyprus and Stanford University map the complex biological cascade caused by MIA: the expression of multiple genes involved in autism are turned up or down by MIA, affecting key aspects of prenatal brain development that may increase risk for atypical development later in life.

“We provide novel evidence that supports the link between prenatal infections and biology known to be important in the development of autism,” said senior author Tiziano Pramparo, PhD, associate research scientist at the Autism Center of Excellence at UC San Diego School of Medicine. “There are different routes of importance. We highlight a specific pathway that seems to be key in driving downstream early abnormal brain development.”

“Our work adds to growing evidence that prenatal development is an important window for understanding key biology of relevance to neurodevelopmental conditions like autism,” added lead author Michael Lombardo, PhD, at the University of Cyprus. “MIA is an environmental route of influence on fundamental biological processes important for brain development. The influence it exerts overlaps with key processes known to be important in how the brain in autism develops.”

Pramparo said the effects are not caused by the infectious agents themselves — virus or bacterium — but from the maternal immune response itself. “Although the mechanisms are not entirely known, it has to do with the cascade of altered events regulating production and function of neurons, their synapses and how they arrange themselves in the brain that are triggered when a mother’s immune system is activated.”

For example, increased levels of maternal cytokines (small signaling molecules driven by the immune response) may directly or indirectly alter gene expression in the fetus’ brain.

“These up- and down-regulated genes may lead to an excess or reduction in the normal amounts of proteins required for normal brain development,” Pramparo said. “Importantly, we have found that MIA-induced effects involve both single genes and pathways (many genes working in a coordinated way to serve some dedicated biological purpose) essential for early fetal neurodevelopment.” Among the large number of genes whose activity is altered by the maternal immune response, are a few that, when mutated, are thought to cause more genetic forms of autism in a small subset of all ASD toddlers.

Image shows the Zika virus.

This is a cryo-electron micrograph of surface proteins of a Zika virus particle. NeuroscienceNews.com image is credited to Protein Data Bank.

Pramparo suggested the findings have multiple clinical implications.

“In general, the more we know and understand about a disrupted mechanism, 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.”

Another implication, he said, is the potential to define the effects and clinical phenotypes based upon the underlying mechanisms: genetic, environmental or both.

“The MIA effects are transient but very potent during fetal development and perhaps even more potent than the effects induced by certain types of mutations in single gene forms of autism. Also, depending on when MIA occurs during gestation, the clinical characteristics may vary. The finding of MIA affecting the expression genes known to be important in autism supports the hypothesis that a genetic-by-environment interaction may lead to amplified effects at the clinical level. For example, more severe cases of autism.”

About this genetics and autism research article

Co-authors include: Hyang Mi Moon, Jennifer Su and Theo D. Palmer, Stanford University; and Eric Courchesne, UC San Diego.

Funding: UC San Diego Altman Clinical and Translational Research Institute, National Institutes of Health, Simons Foundation Autism Research Initiative, Child Health Research Institute at Stanford University funded this study.

Source: Scott LaFee – UCSD
Image Source: NeuroscienceNews.com image is credited to Protein Data Bank.
Original Research: Full open access research for “Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder” by M V Lombardo, H M Moon, J Su, T D Palmer, E Courchesne & T Pramparo in Molecular Psychiatry. Published online March 21 2017 doi:10.1038/mp.2017.15

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UCSD (2017, March 22). How Prenatal Maternal Infections May Affect Genetic Factors in Autism Spectrum Disorder. NeuroscienceNew. Retrieved March 22, 2017 from http://neurosciencenews.com/genetics-autism-maternal-infection-6273/
UCSD “How Prenatal Maternal Infections May Affect Genetic Factors in Autism Spectrum Disorder.” http://neurosciencenews.com/genetics-autism-maternal-infection-6273/ (accessed March 22, 2017).

Abstract

Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder

Vascular abnormalities and inflammation are found in many Alzheimer’s disease (AD) patients, but whether these changes play a causative role in AD is not clear. The factor XII-initiated contact system can trigger both vascular pathology and inflammation and is activated in AD patients and AD mice. We have investigated the role of the contact system in AD pathogenesis. Cleavage of high molecular weight kininogen (HK), a marker for the inflammatory arm of the contact system, is increased in a mouse model of AD, and this cleavage is temporally correlated with the onset of brain inflammation. Depletion of FXII in AD mice inhibited HK cleavage in plasma and reduced neuroinflammation, fibrinogen deposition, and neurodegeneration in the brain. Moreover, FXII-depleted AD mice showed better cognitive function than untreated AD mice. These results indicate that the FXII-mediated contact system activation contributes to AD pathogenesis, and therefore this system may offer novel targets for AD treatment.

“Depletion of coagulation factor XII ameliorates brain pathology and cognitive impairment in Alzheimer’s disease mice” by Zu-Lin Chen, Alexey S. Revenko, Pradeep Singh, A. Robert MacLeod, Erin H. Norris and Sidney Strickland in Blood. Published online March 2017 doi:10.1182/blood-2016-11-753202

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