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Study shows that genetic vulnerability is linked to autism and a change of cell environment

Study shows that genetic vulnerability is linked to autism and a change of cell environment

Autism spectrum disorders can cause a variety of behavioral problems in people. Scientists and doctors are still puzzled by the significant heterogeneity in their symptoms.

While autism was initially suspected to be related to inflammation, a team of researchers from the University of Geneva (UNIGE), Switzerland has decoded how a change of cells environment triggers autistic symptoms. This was done within the Synapsy National Center of Competence and Research.

Indeed, an imbalance in the expression of a series of genes caused by a massive inflammation — resulting from an immune response to the administration of a pharmacological product —leads to the hyperexcitability of neurons of the reward system. 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, a professor at the UNIGE Faculty of Medicine, and director of Synapsy National Center of Competence In Research, led the research team that demonstrated the role of reward systems in the social interaction deficit in autistic mouse models. In fact, the reward system is key to motivating individuals to interact with others. This is achieved through activation of neuronal network.

What are the molecular and cellular mechanisms that cause social interaction deficits? Scientists studied so-called heterozygous mouse models to understand the process and determine how symptoms manifest. Mice that have one of two copies of the SHANK3 gene deleted, but do not display social behavioral disorders, are called heterozygous mice. This is the most common cause of autism with 1-2% of all cases.

One of the two copies of SHANK3 that are essential for communication between neurons and synapses function in humans is missing. Humans have this mutation. However, mice with the disease are not affected by a single copy mutation of SHANK3, which is why they exhibit a variety of behavioral phenotypes.

Camilla Bellone, Professor at the University of Geneva, Department of Basic Neurosciences

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. A number of genes related to inflammation were found, including Trpv4, a gene that is also involved with the functioning of communication channels between neuronal cells. Camilla Bellone stresses that “inducing massive inflammation caused us to observe an overexpression of Trpv4, leading to neuronal hyperexcitability, which then resulted in the onset of social avoidance behavior that our mice didn’t exhibit until now.” The scientists were also able restore normal social behavior by inhibiting Trpv4.

“This evidence suggests that autistic disorder are the result of an interaction between genetic susceptibility, an external trigger, and in this instance, massive inflammation. Neuronal hyperexcitability can disrupt communication channels, altering brain circuits that control social behavior and causing neuronal hyperexcitability. This would also explain why different genetic predispositions can cause a variety of symptoms with varying severity depending on how they are triggered and what type of inflammation they provoke.

Irreversible damage during development?

The inflammation was inducible in adult animals during this study. The resulting deficit in social behavior was not just reversible but also disappeared naturally after a few weeks. “We now need to replicate our research during the critical phases of neurodevelopment — i.e. during gestation and immediately after birth — in order to observe the impact of hyperexcitability on the developing neural networks. Camilla Bellone says that this could cause irreparable damage to neural networks.

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Yan Rosenstein, used with permission

This study proves that inflammation is directly linked to behavioral symptoms in genetic vulnerability. It also highlights the importance environmental factors, which were often overlooked until now.

It also highlights that autistic disorders are still poorly understood. It is possible to find a treatment that corresponds to the specific cellular and molecular modifications in brain circuits by analyzing the gene-environment interactions.

Source:

Journal reference:

Tzanoulinou, S., et al. (2022) Inhibition Trpv4Rescues circuit and social deficiencies are unmasked by acute inflammation in a Shank3 mouse model for Autism. Molecular Psychiatry. doi.org/10.1038/s41380-021-01427-0.

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