Nonclustered Protocadherins in Autism: Integrating Cell Adhesion and Activity-Dependent Signalling

Autism spectrum disorders (ASD) are heterogeneous neurodevelopmental conditions characterized by deficits in social communication and repetitive behaviours, collectively affecting nearly 2% of the global population. ASD is strongly heritable, with genetic variants converging on molecular pathways that regulate synaptic connectivity. Protocadherins, particularly nonclustered protocadherins (ncPCDHs), have emerged as high-confidence ASD-associated genes. By mediating cell surface adhesion and downstream signalling, ncPCDHs regulate essential neurodevelopmental processes ranging from neuronal production and migration to synaptic maturation, while generating combinatorial surface codes that organize circuit wiring-all mechanisms highly relevant to ASD. Here, we review recent findings from human genetics and rodent models, highlighting activity-dependent signalling as a central hub through which ncPCDHs coordinate synaptic refinement and maintain excitatory/inhibitory balance. Finally, we discuss how dissecting ncPCDH molecular mechanisms may clarify ASD pathogenesis and inform targeted therapeutic strategies.