A UNIGE team demonstrates the interplay between genes and environment in autistic disorder, explaining the large variability of the condition’s symptoms.
Autism spectrum disorders are known for their characteristic behavioral difficulties. Scientists and physicians remain puzzled by the significant heterogeneity in their 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 PsychiatryThis is the first evidence that genes and the environment interact in autistic disorders’ social dysfunctions.
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 problems. The reward system activates the neuronal networks, which in turn drives the motivation to interact with peers.
What are the molecular and cellular mechanisms that cause 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 not social behavioural disorder. This is the most common monogenic cause of autism, accounting for 1-2% of all cases.
Camilla Bellone explains that only one of the two copies SHANK3 genes is affected in humans. This mutation is critical for the functioning and communication between neurons and synapses. In animal models [autism]However, mutation of SHANK3 is not enough to alter the behavior of mice. This explains the differences in the observed behavioural phenotypes.
The role of neuronal Hyperexcitability
To identify other genes whose expression was altered, the researchers first inhibited SHANK3’s expression in the reward system’s neural networks. 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 environmental factors and the type or 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. Now, we need to replicate our research during critical phases 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 warns that this could lead to irreparable damage to the neural network construction.
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 highlights that we still need to understand the mechanisms behind autistic disorders in order to intervene effectively. 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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