Protocadherin 19 (PCDH19), PCDH10 and PCDH17 are homophilic cell adhesion molecules that belong to the δ2-protocadherin family. PCDH19 has been implicated in autism spectrum disorder (ASD—category S according to the SFARI Gene scoring system) and epilepsy; PCDH10 has been linked to ASD (category 4); and PCDH17 is associated with mood disorders. Each is highly expressed in the cortex and basal ganglia during development, localizing at synapses. However, the precise roles of these PCDHs in the brain and how mutations in each of these PCDH genes lead to neurodevelopmental and psychiatric disorders remain unknown.

It has been suggested that different cortical areas project to discrete regions of the basal ganglia in a highly topographic manner, creating a parallel organization of functionally segregated circuits, with limbic, associative and sensorimotor circuits. The limbic circuit plays a key role in motivated behavior and empathic/socially appropriate behavior; the associative circuit is implicated in executive functions such as organizing behavioral responses to complex problems and cognitive function; and the sensorimotor circuit plays a role in sensorimotor modulation and movement regulation.

Hisashi Umemori and his colleagues at Boston Children’s Hospital, Harvard Medical School have preliminary evidence that Pcdh19, Pcdh10 and Pcdh17 are expressed in distinct subregions of the mouse and monkey striatum that are implicated in sensorimotor (posterior striatum), limbic (central/ventral) and associative (anterior) circuits, respectively. They propose that distinct δ2-Pcdhs play critical roles in establishing specific cortico-basal ganglia circuits, and as a result, defects in each Pcdh manifest in a distinct disease phenotype.

To test this idea, Umemori’s team has generated novel constitutive and conditional knockout mice for each of the three δ2-Pcdh genes. Umemori’s group will assess these mouse models using histological, imaging, electrophysiological and behavioral approaches to reveal the molecular mechanisms underlying the development of appropriate cortico-basal ganglia circuits. The results of these studies will provide a greater understanding of how mutations in Pcdhs contribute to ASD.