A UNIGE team demonstrates the interplay between genes and environment in autistic disorder, explaining the large variability in the condition’s symptoms.
Autism spectrum disorders are known for their characteristic behavioral difficulties. Scientists and doctors remain puzzled by the large heterogeneity of autism spectrum disorder symptoms. Although autism and inflammation were suspected, a team from the University of Geneva, Switzerland, in the framework of the Synapsy Centre of Competence In Research, has decoded how a change to the cell environment triggers autistic symptoms in mice with a genetic vulnerability. A massive immune response to the administration a pharmacological drug causes a disruption in the expression of several genes that leads to hyperexcitability in reward system neurons. These results can be found in the journal Molecular PsychiatryThe first evidence of the close interaction between genes and environment in social dysfunctions that are typical of autistic disorders is provided by.
Camilla Bellone is a professor at UNIGE Faculty of Medicine. She also directs the Synapsy Centre of Competence and Research. Her research had already shown the role of the reward system as a factor in autistic mice’s social interaction deficit. In fact, the reward system is closely tied to the motivation that drives individuals into interacting with their peers. This is because it activates the neuronal network that makes up the reward system.
But what are the molecular and cell mechanisms that cause the social interaction deficits? Scientists studied so-called heterozygous mouse to better understand the process and determine how symptoms manifest. mice with a deletion of one of two copies of SHANK3 gene but no social behavioural disorder. This is one of the most common causes of autism with 1-2% of all cases.
Camilla Bellone points out that humans have a mutation in one of two copies of SHANK3, a genetic that is essential for the functioning synapses as well as communication between neurons. In animal models [autism]However, mutations of SHANK3 in one copy only slightly alter the behaviour of mice. This explains why the observed behavioural phenotypes are not homogeneous.
The role of neuronal Hyperexcitability
In order to identify other genes whose expression had been altered, the researchers first inhibited SHANK3 expression in neural networks of reward system. Numerous genes that are related to the inflammatory process were identified, including Trpv4, which also plays a role in the functioning and communication of neurons. Camilla Bellone stresses that we were able to induce massive inflammation and observed Trpv4 overexpression. This caused neuronal hyperexcitability, which in turn led to social avoidance behaviors that our mice had not displayed until now. Scientists were able also to restore normal social behaviour after inhibiting Trpv4.
This proves that autistic disorders are caused by an interaction between a genetic susceptibility, an external trigger, and in this instance, massive inflammation. Neuronal hyperexcitability can disrupt communication channels and alter brain circuits that govern social behaviour. This would explain why the same genetic predisposition could lead to a variety of symptoms with varying severity depending on the environment factors and the type inflammation they trigger.
Irreversible damage during development?
The inflammation was inducible in adult animals during this study. The resulting social behavior deficit was not only reverseable, but also disappeared naturally within a few days. Our research must be replicated during the critical stages of neurodevelopment, i.e. To observe the effects of hyperexcitability upon the development of neural networks, we need to replicate our research during the critical phases of neurodevelopment (i.e. Camilla Bellone says this could cause irreparable damage to neural networks.
This study proves that inflammation can cause behavioural symptoms, even in the presence genetic vulnerability. It also highlights how important environmental factors are, which have been greatly underestimated up until now. It also points out that there is still much to learn about the mechanisms behind autistic disorder in order for effective intervention. Based on the individual patient’s gene-environment interactions, and inflammatory mechanisms, it is possible to identify a treatment to match the cellular or molecular modification in the brain circuits.
Refer to: Tzanoulinou S, Musardo S, Contestabile A, et al. Inhibition in Trpv4 rescues circuits and social deficits not masked by acute inflammation response in a Shank3 mouse model Autism. Mol Psychiatry. Published online January 12, 20,22:1-15. doi :10.1038/s41380-021-01427-0
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