Brain Mechanisms of Genetic and Inflammatory Double-Hit Vulnerability to Developmental Social Dysfunctions

The 16p11.2 proximal deletion is a copy number variant (CNV) associated with an increased risk of autism spectrum disorders (ASD), though its phenotypic manifestations vary extensively. The brain mechanisms linking this CNV to social behavioral traits relevant to ASD remain poorly understood, but emerging evidence suggests a key role for immune-brain interactions. Despite the availability of mouse models for 16p11.2 deletion, research on social behavior in this CNV and on the underlying neural mechanisms remains limited. This study employed a series of behavioral tests in 16p11.2 mutant mice and their wild-type littermates to assess sociability, social novelty recognition, social memory, and emotion discrimination. We found that adult mutant mice showed no significant alterations in social behavior, and that an immune challenge in adulthood did not induce genotype-specific deficits. In contrast, 16p11.2 adolescent mice exhibited subtle alterations, such as increased exploration of non-social stimuli, suggesting age-dependent phenotypic changes. Notably, maternal immune activation (MIA) induced sociability deficits in 16p11.2 adolescent mice but not in wild-type littermates, highlighting an underlying increased vulnerability of this genetic condition especially in the prenatal period. To further investigate the developmental processes shaping social behavior in adolescence, microglial depletion in wild-type mice revealed phase-specific effects: depletion in early adolescence impaired emotion discrimination, while depletion in mid-adolescence disrupted both sociability and emotion discrimination. The latter was accompanied by an inversion of the activity patterns of somatostatin-positive neurons in the prelimbic cortex, suggesting a mechanistic link between microglial function and cortical inhibitory neurons activity in social behavior development. Overall, these findings highlight the increased vulnerability of 16p11.2 deletion to perinatal immunological challenges with detrimental effects on social functioning. Future studies will be needed to clarify microglial involvement across development in 16p11.2, as well as the role of inhibitory neuron-microglia interactions following MIA. These efforts aim to deepen our understanding of the neuroimmune mechanisms underlying ASD-related phenotypes and identify potential preventive and therapeutic strategies.