ASD/OCD-Linked Protocadherin-10 Regulates Synapse, But Not Axon, Development in the Amygdala and Contributes to Fear- and Anxiety-Related Behaviors.

The Protocadherin-10 (PCDH10) gene is associated with autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), and major depression (MD). The PCDH10 protein is a homophilic cell adhesion molecule that belongs to the δ2-protocadherin family. PCDH10 is highly expressed in the developing brain, especially in the basolateral nucleus of the amygdala (BLA). However, the role of PCDH10 in vivo has been debatable: one paper reported that a Pcdh10 mutant mouse line showed changes in axonal projections; however, another Pcdh10 mutant mouse line was reported to have failed to detect axonal phenotypes. Therefore, the actual roles of PCDH10 in the brain remain to be elucidated. We established a new Pcdh10 KO mouse line using the CRISPR/Cas9 system, without inserting gene cassettes to avoid nonspecific effects, examined the roles of PCDH10 in the brain, and studied the behavioral consequences of Pcdh10 inactivation. Here, we show that Pcdh10 KO mice do not show defects in axonal development. Instead, we find that Pcdh10 KO mice exhibit impaired development of excitatory synapses in the dorsal BLA. We further demonstrate that male Pcdh10 KO mice exhibit reduced anxiety-related behaviors, impaired fear conditioning, decreased stress-coping responses, and mildly impaired social recognition and communication. These results indicate that PCDH10 plays a critical role in excitatory synapse development, but not axon development, in the dorsal BLA and that PCDH10 regulates anxiety-related, fear-related, and stress-related behaviors. Our results reveal the roles of PCDH10 in the brain and its relationship to relevant psychiatric disorders such as ASD, OCD, and MD.SIGNIFICANCE STATEMENT Protocadherin-10 (PCDH10) encodes a cell adhesion molecule and is implicated in autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), and major depression (MD). PCDH10 is highly expressed in the basolateral nucleus of the amygdala (BLA). However, the phenotypes of previously published Pcdh10 mutant mice are debatable, and some are possibly because of the nonspecific effects of the LacZ/Neo cassette inserted in the mice. We have generated a new Pcdh10 mutant mouse line without the LacZ/Neo cassette. Using our new mouse line, we reveal the roles of PCDH10 for excitatory synapse development in the BLA. The mutant mice exhibit anxiety-related, fear-related, and stress-related behaviors, which are relevant to ASD, OCD, and MD, suggesting a possible treatment strategy for such psychiatric disorders.