Inflammation increases the penetrance of behavioral impairment in Shank3 haploinsufficiency mice — can it explain the behavioral regression in Autism?

Behavioral regression occurs in approximately 40% of individuals with SHANK3-associated autism spectrum disorder (ASD). We previously reported that significant behavioral regression in a small cohort of patients with SHANK3 haploinsufficiency, triggered by subclinical infections, responded to immunomodulator treatments. We hypothesize that behavioral regression results from the interplay between SHANK3 deficiency and neuroinflammation. Using Shank3 exon 4-22 deletion heterozygous mutant (Sh3^+/-) mouse, which shows no significant behavior impairments, we established a preclinical model - Shank3 haploinsufficiency mouse undergoing a systemic inflammation challenge via intraperitoneal injection of lipopolysaccharides (LPS). We found that, two weeks after LPS challenge, wild-type mice (WT) recovered but Sh3^+/- mice exhibited motor impairment, anxiety-like behaviors, and excessive grooming, similar to Shank3 exon 4-22 deletion homozygous mutants. Anti-inflammatory treatment partially reversed LPS-induced behavioral changes. Transcriptomic analysis revealed upregulation of neuroinflammation-related genes and downregulation of synaptic function-related genes in LPS challenged Sh3^+/- mice. Especially, pro-inflammatory genes and microglia markers were overly activated that may result from the increased toll-like receptor 4 (TLR4) in Sh3^+/- mice. Microglia overactivation elevated synapse engulfment and disrupted synaptic protein may underlie LPS-triggered worsen behavior phenotypes in Sh3^+/- mice. Together, our findings indicate that neuroinflammation increases the penetrance of behavioral impairment in Shank3 haploinsufficiency mice and support a potential mechanism for the behavioral regression in human SHANK3 related disorders for future investigations.