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

Abstract

Background 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. Methods 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. Results 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. Limitations 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. Conclusions 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.

Immune activation state modulates infant engram expression across development

“…Immune activation in utero results in the development of an altered brain state where the capacity to form engrams is altered, and infantile amnesia does not occur postnatal immune activation does not seem to affect infantile amnesia, making it plausible that an innate predetermined forgetting switch is fixed from birth. However, interactions between MIA and genetic risk factors for ASD might allow for postnatal inflammation to alter forgetting rates ( 52 , 59 ).…”

Establishment of a two-hit mouse model of environmental factor induced autism spectrum disorder

“…Given the complexity of etiology, researchers started to pay attention to the “two-hit” or “multi-hit” hypothesis in the development of ASD. Several research groups have reported synergistical effects of gene-environment interactions in producing the core syndromes of ASD [ [21] , [22] , [23] ]. In terms of environmental factors, two models, namely simultaneous or cumulative multi-hit have been proposed [ 5 , 24 , 25 ].…”

Neuroplasticity of children in autism spectrum disorder

“…ASD patients have a significant overexpression of histaminergic system-related genes in the brain and chronic neuroinflammation, which may be due to the mechanism that histaminergic system affects neuroinflammation by regulating microglial cell activation, cytokine release, and migration to influence neuroinflammation ( 146 ). MIA during pregnancy exacerbates ASD-like symptoms in Shank3-deficient mice and is accompanied by the upregulation of postsynaptic densitin, impairing the normal functioning of neural pathways ( 147 ). MIA may also increase the risk of ASD by dysregulating aspects of fetal brain gene expression, highlighted by transcriptional dysregulation of mTOR and EIF4E, which affect a variety of key neural developmental functions ( 148 ).…”