Immune activation during pregnancy exacerbates ASD-related alterations in Shank3-deficient mice.

This mouse study looked at how genes and pregnancy infections might work together to cause autism. Researchers found that mice with both a genetic risk factor and exposure to infection-like conditions during pregnancy had worse autism-like behaviors than mice with just the genetic risk. The study suggests that having both genetic vulnerability and pregnancy complications may lead to more severe autism symptoms.

This mouse study investigated the interaction between genetic and environmental factors in autism spectrum disorder (ASD). Researchers combined a genetic mouse model lacking the SHANK3 protein with maternal immune activation during pregnancy to create a 'two-hit' model. The study found that mice exposed to both genetic vulnerability and prenatal immune activation showed more severe autism-like behaviors, including excessive grooming and greater social deficits, compared to mice with only the genetic factor. Unexpectedly, these behavioral changes were accompanied by increased levels of postsynaptic density proteins in key brain regions including the striatum, hippocampus, and prefrontal cortex, suggesting that protein imbalances at synapses may contribute to ASD severity.

Findings suggest that prenatal infections or immune activation may worsen autism outcomes in genetically vulnerable individuals. This supports the importance of prenatal care and infection prevention during pregnancy, particularly for families with genetic autism risk factors.

This is a mouse study with unclear sample sizes, limiting direct translation to humans. The mechanisms behind the observed protein upregulation and behavioral changes remain speculative. The study design and statistical analyses are not detailed in the abstract.

Autism spectrum disorder (ASD) is mainly characterized by deficits in social interaction and communication and repetitive behaviors. Known causes of ASD are mutations of certain risk genes like the postsynaptic protein SHANK3 and environmental factors including prenatal infections. To analyze the gene-environment interplay in ASD, we combined the Shank3Δ11-/- ASD mouse model with maternal immune activation (MIA) via an intraperitoneal injection of polyinosinic/polycytidylic acid (Poly I:C) on gestational day 12.5. The offspring of the injected dams was further analyzed for autistic-like behaviors and comorbidities followed by biochemical experiments with a focus on synaptic analysis.

We show that the two-hit mice exhibit excessive grooming and deficits in social behavior more prominently than the Shank3Δ11-/- mice. Interestingly, these behavioral changes were accompanied by an unexpected upregulation of postsynaptic density (PSD) proteins at excitatory synapses in striatum, hippocampus and prefrontal cortex. We found several PSD proteins to be increased in the two-hit mice; however, we can only speculate about possible pathways behind the worsening of the autistic phenotype in those mice. With this study, we demonstrate that there is an interplay between genetic susceptibility and environmental factors defining the severity of ASD symptoms.

Moreover, we show that a general misbalance of PSD proteins at excitatory synapses is linked to ASD symptoms, making this two-hit model a promising tool for the investigation of the complex pathophysiology of neurodevelopmental disorders.