• 16p11.2 hemideletion (16p11.2 del) increases complement expression in the striatum. • Blocking C3aR signaling ameliorates hyperactivity in 16p11.2 del model mice. • C3aR antagonist reduces interferon stimulated gene levels in 16p11.2 del striatum. The complement system is a major component of the innate immune system and plays an important role in immune surveillance. Recent research has demonstrated that the complement system also plays pivotal roles in brain development, and dysregulation of complement is involved in neurodegenerative and neuropsychiatric disorders. However, the mechanisms by which the complement system contributes to neurodevelopmental disorders (NDDs) remain poorly understood. In this study, we find that the expression of complement components, including complement C3a receptor (C3aR), is upregulated in the striatum of mice modeling the 16p11.2 hemideletion (16p11.2 del). 16p11.2 del is among the most common copy number variations associated with NDDs including attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability (ID). Pharmacological inhibition of C3aR reduces hyperactivity in 16p11.2 del mice, suggesting that potentiated complement signaling contributes to NDD-relevant behavioral changes. Several cytokines are also upregulated in 16p11.2 del mice striatum, a key neural substrate for locomotor behavior, where we also observe morphological and transcriptional indications of reactive microglia. C3aR inhibition suppresses the elevated expression of interferon-stimulated genes in the 16p11.2 del striatum suggesting that crosstalk between complement and interferon signaling may influence microglial state and hyperactivity in 16p11.2 del mice. Collectively, these data indicate that increased expression of the complement system exacerbates hyperactive behavior and is associated with microglial responses in the striatum of 16p11.2 del mice. Our results suggest that inhibition of the complement system may be an effective strategy to ameliorate NDD symptoms resulting from 16p11.2 hemideletion including those associated with ADHD.
Kelvington et al. (Sun,) studied this question.