CNTN6 Modulates Slit-Robo Signaling in Cortical GABAergic Interneuron Migration

Contactin-6 (CNTN6) is a membrane protein that belongs to the contactin subgroup of the immunoglobulin (Ig) superfamily. Substantial evidence supports a significant role of its encoding gene, CNTN6, in neurodevelopment and psychiatric disorders, including autism spectrum disorders and schizophrenia. Further studies are required to clarify the role of CNTN6 in the etiology of these disorders. Here, we show that the first three Ig domains of the extracellular region of CNTN6 compete with Robo2 for binding to the leucine-rich repeat (LRR) domain of Slit2 and inhibit Slit-Robo signaling, thereby regulating neurite outgrowth in cortical neurons. The repulsive effect of Slit2 on the migration of GABAergic neurons was attenuated by the interaction between CNTN6 and Slit2, both in vitro and ex vivo. Male mice deficient in Cntn6 exhibited a significant reduction in the number of calbindin-positive GABAergic neurons in the motor cortex. Cntn6-null male mice also exhibited impaired social recognition and disrupted self-grooming behavior. These findings suggest that CNTN6 inhibits Slit-Robo signaling and modulates the migration of a subset of GABAergic neurons, thereby contributing to the development of autism-related behaviors associated with CNTN6 dysfunction.