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

Area of Science:

• Neuroimmunology
• Developmental Neuroscience

Background:

• The complement system is crucial for innate immunity and immune surveillance.
• Emerging evidence highlights its role in brain development and its dysregulation in neurodevelopmental disorders (NDDs).
• Mechanisms linking complement to NDDs are not fully understood.

Purpose of the Study:

• To investigate the role of the complement system, specifically complement component 3 (C3), in a mouse model of 16p11.2 deletion syndrome, a common genetic cause of NDDs.
• To explore the therapeutic potential of targeting the complement system for NDD-related behavioral changes.

Main Methods:

• Utilized a mouse model of 16p11.2 hemideletion (16p11.2 del).
• Assessed C3 expression in the striatum.
• Administered pharmacological inhibitors of the C3a receptor.
• Analyzed the striatal cytokine environment.

Main Results:

• C3 expression was upregulated in the striatum of 16p11.2 del mice.
• Pharmacological inhibition of the C3a receptor significantly alleviated hyperactivity in these mice.
• Several inflammatory factors were upregulated in the striatum of 16p11.2 del mice, indicating a pro-inflammatory state.

Conclusions:

• Increased complement system activity, particularly C3, contributes to hyperactive behavior in the 16p11.2 del mouse model.
• A pro-inflammatory environment in the striatum is associated with elevated complement.
• Inhibiting the overactive complement system may be a viable strategy to treat NDD symptoms, including those linked to ADHD.