March 2, 2020
A study in mice by the Weizmann Institute of Science suggests how an acute inflammatory immune response in pregnancy may be tied to autism spectrum disorders.
Despite extensive research, scientists are still unsure about the causes of autism spectrum disorders (ASDs) – a broad range of conditions characterized by impaired cognition, difficulties with social interaction and communication, and typical repetitive behaviours. Severe maternal infection during pregnancy has been linked to a higher prevalence of ASD, yet this link remains controversial.
Weizmann Institute of Science’s Professor Orly Reiner and PhD student Lihi Ben-Reuven of the Molecular Genetics Department thought that mimicking viral infections during pregnancy in mice could help determine how these affect brain development in the embryo.
“Although signs of autism usually only first appear around age two or three years, it is considered a neurodevelopmental disease, which suggests that changes could already be ‘brewing’ in the embryonic brain,” said Reiner.
Using a substance that mimics a virus thus activated the pregnant mouse’s immune response. When the activation was carried out on day 12 (out of 18 days of pregnancy in mice), the offspring exhibited autism-like behaviours, and the researchers found that their cortex (the frontal part of the brain) was thicker than usual.
The cortex is the part of the brain where most information processing occurs – including thinking, perceiving, and producing and understanding language. These are also the processes affected in those with ASD.
Taking their study a step further, Reiner and Ben-Reuven investigated what was happening in the embryos’ cortex immediately following activation of the immune response. Surprisingly, they found that more neurons than usual were being ‘born’ as little as six hours following the immune activation.
“In other words, the mother got sick and the embryos were affected,” explained Ben-Reuven.
The researchers also discovered that the production of additional neurons was limited to a 48-hour time window.
But which neurons were being overproduced? And how?
Previous studies had demonstrated that following activation of the mothers’ immune response, there is an increase in the levels of a signalling molecule called interleukin 6 (IL6). IL6 is known to be linked to inflammation caused by viruses. But it can also increase the ‘birth rate’ of brain cells.
In the current study, the scientists noticed that the increased levels of IL6 right away shortened the cell cycles of the neuron-producing stem cells in the embryos’ cortex. As a result, more neurons were generated in this part of embryonic brain.
As the embryonic brain develops, the cortex organises itself into six layers. Each layer is composed of particular types of neurons, and these have complicated patterns of connections.
The production of the different types of neurons is guided by transcription factors – proteins that help to turn specific genes ‘on’ or ‘off’. The researchers found increased levels of a particular transcription factor, which in turn resulted in an overproduction of a specific type of neuron. These neurons are the CTIP2+ neurons that are found in layer five of the cortex.
“As a result, at the end of pregnancy and in the young mice, the offspring have a relatively larger cortex and a thickened layer five,” explained Ben-Reuven.
“These offspring displayed abnormal behaviour, and we could now tie this behaviour to the acute immune activation during a particular developmental stage. Our ability to discover the overproduction of specific types of neurons in an autism model is really interesting.”
This research was recently published in Molecular Psychiatry. Overall, it lends support to the notion that an acute inflammatory immune response ‒ during a specific time window in pregnancy ‒ does, indeed, affect embryonic brain development. With regard to humans, Reiner cautioned: “Increased brain size has been found in a subgroup of autism patients. Whether or not there is a direct correlation, time will tell, but if a link is proven in the future, we are talking about a very short and a very severe infection – not something like the common cold.”
Lihi Ben-Reuven and Professor Orly Reiner
Cross sections of embryo cortex at day 18 of pregnancy (left), compared to an embryo from the maternal immune activation group (right). The green shows cells in the fifth layer of the brain (CTIP2+ neurons), which are overproduced in those of the immune response group. Scale bar: 20 micrometers