Summary: Inducing massive inflammation resulted in overexpression of Trpv4. The overexpression led to neural hyperexcitability that resulted in social avoidance behaviors associated with ASD in mouse models.
Source: University of Geneva
The research team led by Camilla Bellone, a professor in the Department of Basic Neurosciences at the UNIGE Faculty of Medicine and director of the Synapsy National Centre of Competence in Research, 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, through the activation of the neuronal networks that make it up.
But what are the cellular and molecular mechanisms at the origin of the deficits in social interaction?
To understand this process and thus decipher how the symptoms appear, the scientists studied so-called heterozygous mice, i.e. mice carrying a deletion of only one of the two copies of the SHANK3 gene, but not showing social behavioural disorders. With 1-2% of all autism cases, this is indeed one of the most common monogenic causes of the disease.
“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 behaviour of mice, which explains why the behavioural 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 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.
Inhibition of Trpv4 rescues circuit and social deficits unmasked by acute inflammatory response in a Shank3 mouse model of Autism
Mutations in the SHANK3 gene have been recognized as a genetic risk factor for Autism Spectrum Disorder (ASD), a neurodevelopmental disease characterized by social deficits and repetitive behaviors. While heterozygous SHANK3 mutations are usually the types of mutations associated with idiopathic autism in patients, heterozygous deletion of Shank3 gene in mice does not commonly induce ASD-related behavioral deficit.
Here, we used in-vivo and ex-vivo approaches to demonstrate that region-specific neonatal downregulation of Shank3 in the Nucleus Accumbens promotes D1R-medium spiny neurons (D1R-MSNs) hyperexcitability and upregulates Transient Receptor Potential Vanilloid 4 (Trpv4) to impair social behavior. Interestingly, genetically vulnerable Shank3+/− mice, when challenged with Lipopolysaccharide to induce an acute inflammatory response, showed similar circuit and behavioral alterations that were rescued by acute Trpv4 inhibition.
Altogether our data demonstrate shared molecular and circuit mechanisms between ASD-relevant genetic alterations and environmental insults, which ultimately lead to sociability dysfunctions.