Cadherins and neuropsychiatric disorders

Cadherins mediate cell-cell adhesion but are also involved in intracellular signaling pathways associated with neuropsychiatric disease. Most of the ∼100 cadherins that are expressed in the brain exhibit characteristic spatiotemporal expression profiles. Cadherins have been shown to regulate neural tube regionalization, neuronal migration, gray matter differentiation, neural circuit formation, spine morphology, synapse formation and synaptic remodeling. The dysfunction of the cadherin-based adhesive system may alter functional connectivity and coherent information processing in the human brain in neuropsychiatric disease. Several neuropsychiatric disorders, such as epilepsy/mental retardation, autism, bipolar disease and schizophrenia, have been associated with cadherins, mostly by genome-wide association studies. For example, CDH15 and PCDH19 are associated with cognitive impairment; CDH5, CDH8, CDH9, CDH10, CDH13, CDH15, PCDH10, PCDH19 and PCDHb4 with autism; CDH7, CDH12, CDH18, PCDH12 and FAT with bipolar disease and schizophrenia; and CDH11, CDH12 and CDH13 with methamphetamine and alcohol dependency. To date, disease-causing mutations are established for PCDH19 in patients with epilepsy, cognitive impairment and/or autistic features. In conclusion, genes encoding members of the cadherin superfamily are of special interest in the pathogenesis of neuropsychiatric disease because cadherins play a pivotal role in the development of the neural circuitry as well as in mature synaptic function.