Modelling monogenic autism spectrum disorder using mouse cortical organoids
Sai Hali1, Jonghun Kim2, Tae Hwan Kwak1
1Department of Stem Cell Biology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea; Department of Neuroscience, School of Medicine and Center for Neuroscience Research, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul, 143-701, Republic of Korea.
Abstract:
Variants of the contactin-associated protein-like 2 (CNTNAP2), which is a member of the neurexin family of proteins, function as cell adhesion molecules. The loss of CNTNAP2 function leads to autism spectrum disorder in humans and to autistic behaviours in mice. However, the functional effects of these mutations at the cellular level during fetal developmental periods remain elusive. Here, we studied mouse cortical organoids (mCOs) derived from Cntnap2-/- (knockout, KO) mouse induced pluripotent stem cells (miPSCs). Our results showed that KO mCOs displayed inhibitory-neuron-specific defects. At the neural progenitor stage, the GABAergic-neurogenesis-governing transcriptional network was dysregulated in the absence of Cntnap2. Our findings suggest that, in the early fetal cortical development, the cell adhesion molecule Cntnap2 plays a crucial role in the regulation of the differentiation of GABAergic neurons in the organoid platform. The reduced number of GABAergic neurons was efficiently restored in KO mCOs by treatment with the antiepileptic drug retigabine, showing the effectiveness of Cntnap2 KO mCOs in the therapeutic targeting of ASD.
Insights
Loss of contactin-associated protein-like 2 (CNTNAP2) disrupts GABAergic neuron development in fetal brain organoids. Restoring CNTNAP2 function in these autism spectrum disorder models offers therapeutic potential.
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.
