Anterior insular cortex regulates depression-like and ASD-like behaviors via the differential contribution of two subsets of microglia.

Scientists studied brain immune cells called microglia in mouse models of autism and depression. They found that two different types of microglia in a brain region called the anterior insular cortex play different roles. One type was linked to autism-like social problems and repetitive behaviors, while the other was connected to depression-like symptoms. The researchers also identified specific proteins that these immune cells release that contribute to these behavioral differences.

This preclinical study investigated how two distinct microglia subpopulations in the anterior insular cortex contribute to autism-like and depression-like behaviors in mouse models. Using Cntnap2-deficient mice (autism model) and chronic social defeat stress-induced mice (depression model), researchers found that Cx3cr1+ microglia were morphologically altered in autism-like conditions and linked to social deficits and repetitive behaviors, while Tmem119+ microglia showed changes in depression-like conditions and affected reward-related behaviors. The study identified specific secretory factors (Fbl and Hp1bp3) that mediate these microglial dysfunctions. These findings provide mechanistic insights into how brain immune cells may differentially contribute to autism and depression phenotypes.

While promising for understanding neuroinflammatory mechanisms, these findings are preliminary and require human validation. The identification of distinct microglial pathways may eventually inform targeted interventions, but clinical translation remains distant given the early-stage preclinical nature of this research.

This is preclinical research using mouse models, limiting direct translation to humans. Sample sizes are not reported, making it difficult to assess statistical power. The study design type is unclear from the abstract, and findings require validation in human studies.

The anterior insular cortex (aIC) is involved in multiple neuropsychiatric disorders. Here, using the Cntnap2-deficient autism spectrum disorder (ASD) mouse model and the chronic social defect stress (CSDS)-induced depression mouse model, we show that two subpopulations of microglia in the mouse aIC played differential roles in ASD-like and depression-like behavioral phenotypes differentially. The Cx3cr1microglia had morphological deficits in the Cntnap2-deficient mice and were involved in social deficits and restricted repetitive behaviors, while the Tmem119microglia had morphological deficits in the CSDS-induced mice and contributed to impairments in sucrose preference and forced swim performance. Further, we showed that the two subsets of microglia had differential features in morphology, transcriptional profiles, electrophysiological properties, and impacts on synaptic functions.

Using proteomic and metabonomic analyses, we identified two secretory factors, Fbl and Hp1bp3, that were crucial for the dysfunctions of the Cx3cr1and Tmem119microglia, respectively. Finally, we verified that Fbl and Hp1bp3 played essential roles in the behavioral deficits of the Cntnap2-deficient and the CSDS-induced mice, respectively. Our study can help understand the contribution of microglia and the aIC to neuropsychiatric-like behaviors.