The knockout of Moesin leads to excess microglia-mediated synaptic pruning and impairs social novelty in a mouse model.

Scientists studied mice that were missing a gene called Moesin, which has been linked to autism in humans. These mice showed autism-like behaviors including problems with social interaction and repetitive behaviors. The researchers found that without this gene, brain cells called microglia became overactive and removed too many connections between brain cells. When they treated the mice with a specific antibody, it helped restore normal brain function and improved social behaviors.

This preclinical study investigated the role of Moesin (MSN) gene in autism spectrum disorders using knockout mice. Researchers found that mice lacking the Moesin gene exhibited impaired social novelty recognition and repetitive behaviors, key characteristics of autism. The mechanism involved increased microglial activation leading to excessive synaptic pruning in the medial prefrontal cortex through C1q-dependent pathways. Treatment with IFNAR1 antibody rescued both the microglial abnormalities and social deficits, suggesting a potential therapeutic target.

The study provides mechanistic insight into how MSNP1AS, previously identified in genome-wide association studies as autism-associated, may contribute to autism through interferon signaling and synaptic dysfunction.

The findings suggest that interferon signaling pathways and microglial function may be therapeutic targets for autism. However, this is early preclinical research requiring human validation studies before any clinical applications can be considered.

This is a preclinical mouse study with unclear sample sizes. Translation to human autism requires validation. The study focuses on one specific gene pathway and may not represent the broader heterogeneity of autism spectrum disorders.

Genome-wide association studies (GWASs) have implicated a noncoding antisense RNA designated as MSNP1AS (Moesin pseudogene 1, antisense) in susceptibility to autism spectrum disorders (ASDs). MSNP1AS binds to and downregulates the Moesin (Msn) transcript and is highly overexpressed in the postmortem cerebral cortex of individuals with ASDs. However, the mechanistic link between Msn loss in vivo and ASD-related phenotypic traits remains enigmatic. Here, we generate Msn knockout (KO) mice, on which neurobehavioral tests reveal impaired social novelty and repetitive behaviors.

Msn KO activates the microglial population, leading to aberrant C1q-dependent synaptic pruning followed by synaptic deficits in the medial prefrontal cortex. The aberrant regulatory pathway can be rescued by IFNAR1 antibody, which rescues microglial abnormalities and social deficits. Taken together, the results of the current study reveal a pathway in which Msn mediates interferon signaling and synaptic pruning to affect ASD-like behaviors, providing a functional genetic link between MSN and neurobehavioral abnormalities.