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. (C) 2019 Elsevier Inc. All rights reserved.