Putative complement control protein CSMD3 dysfunction impairs synaptogenesis and induces neurodevelopmental disorders

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Complement-related proteins influence cortical synapse development.
• The specific role of CSMD3 in the central nervous system and synaptogenesis is largely unknown.
• CSMD3 is a putative complement control protein.

Purpose of the Study:

• To investigate the role of CSMD3 in neurodevelopment and neurodevelopmental disorders (NDDs).
• To explore the function of CSMD3 in synaptogenesis and neuronal development within the central nervous system.

Main Methods:

• Analysis of CSMD3 mutations in patients with NDDs.
• Investigating Csmd3 expression patterns in the developing mouse cortex.
• Phenotypic analysis of Csmd3-disrupted mice, including behavioral assessments and examination of neurogenesis and synaptogenesis.

Main Results:

• Deleterious CSMD3 mutations were frequently identified in NDD patients.
• Csmd3 is highly expressed in developing cortical neurons.
• Csmd3 disruption in mice led to developmental delays, NDD-related behaviors, impaired synaptogenesis, reduced neurogenesis, and altered cortical network activity.
• Gene expression changes included downregulation of synapse-associated genes and upregulation of immune-related genes.

Conclusions:

• CSMD3 plays a critical role in mammalian brain development and synaptogenesis.
• CSMD3 mutations are implicated in the pathology of neurodevelopmental disorders.
• This study provides mechanistic insights into complement-related protein regulation in synaptic development.