Dr. Bellone discusses how mutations in the SHANK3 gene are a recognized genetic risk factor for Autism Spectrum Disorder (ASD).
It's noted that while these mutations are typically associated with autism in humans, mice with heterozygous deletion of the Shank3 gene don't typically show ASD-like behaviors.
1. Role of the Shank3 gene in mice:
- Downregulating the Shank3 gene in the Nucleus Accumbens of neonatal mice results in increased excitability in specific neurons and impairs social behavior.
- When genetically vulnerable mice are exposed to inflammation, they display similar behavioral changes. These changes can be reversed with acute inhibition of a particular receptor (Trpv4).
2. Importance of the Nucleus Accumbens in ASD:
- Human studies have shown that the Nucleus Accumbens (NAc) is activated by social stimuli, and this activation is disrupted in ASD patients.
- The activity of the direct pathway in the NAc is crucial for social behavior. Both increased, and decreased activity can lead to reduced sociability in mice.
3. The role of the environment and critical developmental periods:
- Synaptic connections and brain circuits undergo changes during developmental "critical periods". How these critical periods affect ASD is still being explored.
- Early downregulation of Shank3 in the NAc leads to social deficits. However, Shank3 downregulation in adulthood does not have the same impact.
4. Connection between Shank3 and Trpv4:
- Loss of Shank3 increases the expression of Trpv4. Trpv4 plays a role in calcium signaling and affects neuronal excitability.
- Trpv4 upregulation was specifically observed in young mice with Shank3 downregulation but not in older mice.
- Inflammation in Shank3+/− mice resulted in increased Trpv4 expression, which was connected to behavioral deficits. Blocking Trpv4 helped mitigate these deficits.
5. Immune system and ASD:
- Inflammation and immune system activation have been connected to ASD in several studies.
- Dr. Bellone's team found that inducing inflammation in genetically predisposed mice resulted in transient social deficits, suggesting a potential interplay between genetic vulnerability and immune response.
6. Potential therapeutic implications:
- Trpv4 has emerged as a novel potential therapeutic target for addressing social deficits in ASD.
- The relationship between immune response, genetics, and neuronal activity in ASD points to potential avenues for treatments.
The research underscores the intricate interplay between genetics, the environment, and neuronal activity in the context of ASD. Region-specific ablation of Shank3 in mice offers insights into the mechanisms underlying autism-related symptoms and points to potential therapeutic interventions.
https://doi.org/10.1038/s41380-021-01427-0