Autism spectrum disorders are known for their characteristic behavioral difficulties. Scientists and physicians are still trying to understand the heterogeneity of autism spectrum disorders’ symptoms.
Although autism and inflammation were suspected to be linked, a team from the University of Geneva, Switzerland (UNIGE), has discovered how a change of cell environment triggers autistic symptoms in mice with a genetic vulnerability.
Indeed, an imbalance in the expression of a series of genes caused by a massive inflammationresulting from an immune response to the administration of a pharmacological productleads to the hyperexcitability of neurons of the reward system. These results can be found in the journalMolecular PsychiatryThis is the first evidence that genes and environment interact in autistic disorders.
Camilla Bellone, a professor at the UNIGE Faculty of Medicine in the Department of Basic Neurosciences and director of Synapsy National Center of Competence In Research, led the research team that demonstrated the importance of the reward system in the success of the research.Social interactiondeficit in autistic mice Indeed, the motivation to interact with others is closely tied to the reward system through activation of the neuronal network that makes it up.
But what about the cellular?molecular mechanismsWhere is the source of the social interaction deficits? Scientists studied heterozygous mice (i.e. mice that have one of the two copies of the SHANK3 gene deleted) to understand the process and determine how symptoms manifest. Mice with a deletion in one of the two copies SHANK3 genes, but no social behavioral disorders, were studied by scientists. This is the most common monogenic cause of autism, accounting for 1-2% of all cases.
“Humans carry a mutation in only one of the two copies of SHANK3, a gene that is essential for the functioning of synapses and communication between neurons,” points out Camilla Bellone. “In animal models of the disease, however, mutation of a single copy of SHANK3 only slightly affects the behavior of mice, which explains why the behavioral phenotypes observed are not homogeneous”.
Neuronal hyperexcitability: What is its role?
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. “By inducing massive inflammation, we observed an overexpression of Trpv4, which then led to a neuronal hyperexcitability concomitant to the onset of social avoidance behaviors that our mice did not exhibit until now,” stresses Camilla Bellone. Scientists were also able to restore normal social behavior by inhibiting Trpv4.
“This provides evidence that autistic disorders are indeed the result of an interaction between aGenetic susceptibilityAn external trigger, in this instance, massive inflammation. Neuronal hyperexcitability disrupts communication channels, thereby altering the brain circuits governing social behavior.” This would also explain why the sameGenetic predispositionDepending on the circumstances, it can lead to success.environmental factorsTo treat a variety of symptoms with equally variable severity, it is important to know what inflammation they cause and how they are treated.
Irreversible damage during development?
The inflammation was inducible in adult animals during this study. The resulting deficits in social behavior were not only reversible but also disappeared naturally after a few weeks. “We now need to replicate our research during the critical phases of neurodevelopmenti.e. Hyperexcitability can be observed during pregnancy and immediately after birth to assess the impact on developing neural networks. This could damage the construction of neural networks beyond repairs,” says Camilla Bellone.
This study provides proof-of-principle that inflammation is directly related to behavioral symptoms in the presence genetic vulnerability. It also highlights the importance environmental factors, which were largely overlooked until now. It also highlights that we still need to understand the mechanisms behind autistic disorders in order to intervene effectively. 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.