Modelling monogenic autism spectrum disorder using mouse cortical organoids.

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• Contactin-associated protein-like 2 (CNTNAP2) is a cell adhesion molecule crucial for neuronal development.
• CNTNAP2 variants are linked to autism spectrum disorder (ASD) in humans and autistic behaviors in mice.
• Cellular mechanisms underlying CNTNAP2's role during fetal development are not fully understood.

Purpose of the Study:

• To investigate the cellular and molecular functions of CNTNAP2 during early fetal cortical development.
• To utilize mouse cortical organoids (mCOs) as a model to study CNTNAP2 deficiency.

Main Methods:

• Generation of Cntnap2 knockout (KO) mouse cortical organoids from induced pluripotent stem cells.
• Analysis of neural progenitor cells and GABAergic neurogenesis in KO mCOs.
• Transcriptional network analysis to identify dysregulated pathways.

Main Results:

• KO mCOs exhibited specific defects in inhibitory neuron development.
• The transcriptional network regulating GABAergic neurogenesis was dysregulated in the absence of CNTNAP2.
• A reduction in GABAergic neurons was observed in KO mCOs.

Conclusions:

• CNTNAP2 is essential for the proper differentiation of GABAergic neurons during early fetal cortical development.
• CNTNAP2 deficiency leads to specific neurodevelopmental deficits relevant to ASD.
• Mouse cortical organoids serve as a viable platform for studying ASD pathogenesis and therapeutic targeting.