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

Behavioral regression occurs in ~40% of -associated autism spectrum disorder (ASD). We previously reported that significant behavioral regression in a small cohort with haploinsufficiency patients, triggered by subclinical infections, responded to immunomodulator treatments. We hypothesize that behavioral regression results from the interplay between deficiency and neuroinflammation. Using exon 4-22 deletion heterozygous mutant ( ) mouse, which shows no significant behavior impairments, we established a preclinical model - haploinsufficiency mouse undergoing systemic inflammation challenge via intraperitoneal injection of lipopolysaccharides (LPS). We found that, two weeks after LPS challenge, wild-type mice (WT) recovered but mice exhibited motor impairment, anxiety-like behaviors, and excessive grooming, similar to 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 mice in response to LPS. Especially, pro-inflammatory genes and microglia markers were overly activated that may result from the increased Toll-Like Receptor 4 (TLR4) expression in microglia in mice. Our findings indicate that neuroinflammation increases the penetrance of behavioral impairment in haploinsufficiency mice and support a potential mechanism for the behavioral regression in human disorders for future investigations.