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 related 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 a neuronal hyperexcitability concomitant to the onset of social avoidance behaviours that our mice did not exhibit until now,” stresses Camilla Bellone. Moreover, by inhibiting Trpv4, the scientists were able to restore normal social behaviour.
“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. Neuronal hyperexcitability disrupts communication channels, thereby altering the brain circuits governing social behaviour.”
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, the inflammation was induced in adult animals. The resulting deficit in social behaviour was not only reversible, but also disappeared naturally after a few days. “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.
This could damage the construction of neural networks beyond repairs,” says Camilla Bellone.
This study constitutes a proof-of-principle of a direct causality between inflammation and the appearance of behavioural symptoms in the presence of genetic vulnerability, and highlights the importance of environmental factors, which have been largely underestimated until now.
It also highlights the fact that the understanding of the mechanisms behind autistic disorders still needs to be refined in order to intervene effectively. Indeed, depending on the gene-environment interactions and 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 stake in the brain circuits.
People with autism spectrum disorders all have characteristic behavioural difficulties. Nevertheless, the important heterogeneity of their symptoms remains one of the major questions for scientists and physicians.
