Complement contributes to hyperactive behavior in the 16p11.2 hemideletion mouse model

Benjamin A. Kelvington; Jaekyoon Kim; Regan Fair; Marie E. Gaine; Ted Abel

doi:10.1016/j.bbi.2026.106552

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Complement contributes to hyperactive behavior in the 16p11.2 hemideletion mouse model

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Complement contributes to hyperactive behavior in the 16p11.2 hemideletion mouse model

Benjamin A. Kelvington, Jaekyoon Kim, Regan Fair, Marie E. Gaine and Ted Abel

Brain, behavior, and immunity, Vol.136, 106552

08/2026

DOI: 10.1016/j.bbi.2026.106552

PMID: 41881165

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Abstract

•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.

Hyperactivity

Inflammation

16p11.2

Complement

Interferon

Microglia

Neurodevelopmental disorders

Striatum

Details

Title: Subtitle: Complement contributes to hyperactive behavior in the 16p11.2 hemideletion mouse model
Creators: Benjamin A. Kelvington - University of Iowa
Jaekyoon Kim - University of Iowa, Neuroscience and Pharmacology
Regan Fair - University of Iowa
Marie E. Gaine - University of Iowa
Ted Abel - University of Iowa
Resource Type: Journal article
Publication Details: Brain, behavior, and immunity, Vol.136, 106552
DOI: 10.1016/j.bbi.2026.106552
PMID: 41881165
NLM abbreviation: Brain Behav Immun
ISSN: 0889-1591
eISSN: 1090-2139
Publisher: Elsevier Inc
Grant note: National Institutes of Health: NIH F31 MH134542, NIH T32 GM067795, R01 MH087463, R01 DA056113 University of Iowa Hawkeye Intellectual and Developmental Disabilities Research Center (HAWK-IDDRC): NIH P50 HD103556 Roy J. Carver Directorship of the Iowa Neuroscience InstituteNeural Circuits and Behavior Core in the Iowa Neuroscience Institute
Support for this work was provided by the National Institutes of Health (NIH F31 MH134542, NIH T32 GM067795, NIH R01 MH087463, NIH R01 DA056113) and the University of Iowa Hawkeye Intellectual and Developmental Disabilities Research Center (HAWK-IDDRC, NIH P50 HD103556) . TA is supported by the Roy J. Carver Directorship of the Iowa Neuroscience Institute. We thank Drs. Annie Vogel Ciernia and Jennifer Kim for their guidance in analyzing microglia using their MicrogliaMorphology package. We thank Dr. Ildiko Dunay for her sug-gestions pertaining to transcriptional analyses of microglia. We would also like to acknowledge the Neural Circuits and Behavior Core in the Iowa Neuroscience Institute, which provided equipment and facilities to support behavioral and imaging experiments. Figures created with BioRender.com .
Language: English
Date published: 08/2026
Academic Unit: Molecular Physiology and Biophysics; Psychiatry; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
Record Identifier: 9985149573402771

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