The symptoms of autism are very varied, but all people with an autism spectrum disorder (ASD) present certain characteristic behaviors that make their social relationships difficult. For years, science has tried to find out the origin of these problems and it was thought that there was a link between the inflammatory process and autism. Now scientists at the University of Geneva, as part of the Synapsy National Research Center, have found for the first time in mice carrying a genetic vulnerability how a change in the cellular environment triggers the appearance of autistic symptoms.
Specifically, it is an imbalance in the expression of a series of genes as a result of massive inflammation, which occurs as a result of an immune response to the administration of a pharmacological product, which then leads to hyperexcitability of neurons in the reward system. The research findings constitute initial evidence of the influence of close gene-environment interactions on the social dysfunctions that characterize autistic disorders.
It seems that the motivation that drives people to interact with their peers is closely linked to the reward system through the activation of the neural networks that form it. For this reason, the group of researchers led by Camilla Bellone, professor at the Department of Fundamental Neurosciences at the Faculty of Medicine of the University of Geneva (UNIGE) and director of the Sinapsia Pole, had already pointed out the role played by the reward system in the deficit of social interactions in mouse models of autism.
“This provides evidence that autistic disorders are, in fact, the result of an interaction between genetic susceptibility and an external trigger, here massive inflammation.”
To determine the cellular and molecular mechanisms that intervene in these neural networks and influence the origin of the deficits in social interactions, and to understand this process in order to find out how the symptoms appear, the researchers studied the so-called heterozygous mice, which are carriers of a deletion of only one of the two copies of the SHANK3 gene, but who did not have any social behavior disorder. With between 1 and 2% of all cases of autism, it is in fact one of the most common monogenic causes of the disorder.
“Human beings present the mutation in only one of the two copies of SHANK3, an essential gene for the functioning of synapses and for communication between neurons”, pointed out Camilla Bellone. “However, in animal models of the disease, the single-copy mutation of SHANK3 only mildly affects the behavior of mice, which explains why the observed behavioral phenotypes are not homogeneous.”
Neuronal hyperexcitability associated with social avoidance behaviors
To carry out this study, which has been published in Molecular Psychiatry, its authors first inhibited the expression of SHANK3 in the neural networks of the reward system to discover other genes whose expression was modified. These were several genes related to the inflammatory system, and one of them in particular, Trpv4, which was also involved in the functioning of communication channels between neurons.
“By inducing massive inflammation, we observed an overexpression of Trpv4, which caused neuronal hyperexcitability at the same time as the appearance of social avoidance behaviors that our mice had not shown until now”, highlights Camilla Bellone. However, inhibiting Trpv4 allowed normal social behavior to be restored.
“This provides evidence that autistic disorders are, in fact, the result of an interaction between genetic susceptibility and an external trigger, here massive inflammation. Neuronal hyperexcitability interrupts communication channels, thus altering the brain circuits that govern social behaviors. This would also explain why the same genetic predisposition can give rise, depending on the environmental factors found and the type of inflammation they trigger, to a variety of symptoms with equally variable severity”.
Depending on the gene-environment interactions and the specific inflammatory mechanisms of each patient, the type of treatment could be determined
The researchers induced inflammation in adult mice and found that not only was it possible to reverse the deficit it produced in their social behavior, but it also disappeared naturally after a few days. “Now we need to replicate our research during critical phases of neurodevelopment, during gestation, and immediately after birth, to observe the impact of hyperexcitability on the development of neural networks. In fact, this could irreparably damage the construction of neural networks”, explained Camilla Bellone.
The results of the study prove that there is a direct causality between inflammation and the appearance of behavioral symptoms in the presence of a genetic vulnerability, and highlight the importance of environmental factors, which until now had not been sufficiently valued. He also shows that it is necessary to deepen our knowledge of the mechanisms present at the origin of autism spectrum disorders in order to carry out more effective interventions. Thus, depending on the gene-environment interactions and the specific inflammatory mechanisms of each patient, the type of treatment that would correspond exactly to the cellular and molecular modification that intervenes in the brain circuits could be determined.
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