How genes and environment combine to produce autism complexity

A UNIGE team shows how genes and the environment interact in autistic disorders, thus explaining the great variability of the symptoms of the disease.

People with autism spectrum disorders all have characteristic behavioral difficulties. Nevertheless, the significant heterogeneity of their symptoms remains one of the major questions for scientists and physicians. While a link between the inflammatory process and autism was suspected, a team from the University of Geneva (UNIGE), in Switzerland, within the framework of the Synapsy national research center, has for the first time deciphered how a modification of the cellular environment triggers the onset of autistic symptoms in mice with genetic vulnerability. Indeed, an imbalance in the expression of a series of genes caused by massive inflammation – resulting from an immune response to the administration of a pharmacological product – leads to the hyperexcitability of the neurons of the reward system. These results, to be read in the journal Molecular psychiatry, provide the first evidence of the close interactions between genes and environment in the social dysfunctions typical of autistic disorders.

The research team led by Camilla Bellone, professor in the Department of Basic Neurosciences of the UNIGE Faculty of Medicine and director of the Synapsy national research center, had already demonstrated the role of the reward system in the social interaction deficit in autistic mice. Indeed, the motivation that drives individuals to interact with their peers is closely linked to the reward system, via the activation of the neural networks that compose it.

But what are the cellular and molecular mechanisms at the origin of social interaction deficits? To understand this process and thus decipher the appearance of symptoms, the scientists studied so-called heterozygous mice, that is to say mice carrying a deletion of only one of the two copies of the SHANK3 gene, but not presenting no social behavior problems. With 1-2% of all cases of autism, it is indeed one of the most common monogenic causes of the disease.

“Humans are carriers of a mutation in only one of the two copies of SHANK3, a gene essential for the functioning of synapses and communication between neurons”, specifies Camilla Bellone. “In animal models of [autism], however, the mutation of a single copy of SHANK3 only slightly affects the behavior of the mice, which explains why the behavioral phenotypes observed are not homogeneous”.

The role of neuronal hyperexcitability

The researchers first inhibited the expression of SHANK3 in the neural networks of the reward system in order to identify the other genes whose expression was modified. Several genes linked to the inflammatory system were detected, including one of them, Trpv4, which is also involved in the functioning of communication channels between neurons. “By inducing massive inflammation, we observed an overexpression of Trpv4, which then led to neuronal hyperexcitability concomitant with the appearance of social avoidance behaviors that our mice did not present until now”, emphasizes Camilla Bellone. Additionally, by inhibiting Trpv4, the scientists were able to restore normal social behavior.

“This provides evidence that autistic disorders are indeed the result of an interaction between a genetic susceptibility and an external trigger – in this case, massive inflammation. Neural hyperexcitability disrupts communication channels, thereby altering the brain circuits governing social behavior This would also explain why the same genetic predisposition can lead, depending on the environmental factors encountered and the type of inflammation they trigger, to a diversity of symptoms of equally variable severity.

Irreversible damage during development?

In this study, inflammation was induced in adult animals. The resulting deficit in social behavior was not only reversible, but also disappeared naturally after a few days. “We now need to replicate our research during critical phases of neurological development, i.e., during gestation and immediately after birth, to observe the impact of hyperexcitability on developing neural networks. This could damage the construction of neural networks beyond repairs,” explains Camilla Bellone.

This study constitutes proof of principle of a direct causality between inflammation and the appearance of behavioral symptoms in the presence of genetic vulnerability, and highlights the importance of environmental factors, largely underestimated until now. It also highlights the fact that the understanding of the mechanisms at the origin of autistic disorders must still be refined in order to intervene effectively. Indeed, depending on the gene-environment interactions and the inflammatory mechanisms specific to each patient, it would be possible to identify a treatment that would correspond exactly to the cellular and molecular modification at play in the brain circuits.

Reference: Tzanoulinou S, Musardo S, Contestabile A, et al. Inhibition of Trpv4 rescues the circuitry and social deficits unmasked by an acute inflammatory response in a Shank3 mouse model of autism. Mol Psychiatry. Published online January 12, 2022: 1-15. doi:10.1038/s41380-021-01427-0

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Sharon D. Cole