Impact of the ADHD-susceptibility gene CDH13 on development and function of brain networks

Attention-deficit/hyperactivity disorder (ADHD) is a common, early onset and enduring neuropsychiatric disorder characterized by developmentally inappropriate inattention, hyperactivity, increased impulsivity and motivational/emotional dysregulation with similar prevalence rates throughout different cultural settings. Persistence of ADHD into adulthood is associated with considerable risk for co-morbidities such as depression and substance use disorder. Although the substantial heritability of ADHD is well documented the etiology is characterized by a complex coherence of genetic and environmental factors rendering identification of risk genes difficult. Genome-wide linkage as well as single nucleotide polymorphism (SNP) and copy-number variant (CNV) association scans recently allow to reliably define aetiopathogenesis-related genes. A considerable number of novel ADHD risk genes implicate biological processes involved in neurite outgrowth and axon guidance. Here, we focus on the gene encoding Cadherin-13 (CDH13), a cell adhesion molecule which was replicably associated with liability to ADHD and related neuropsychiatric conditions. Based on its unique expression pattern in the brain, we discuss the molecular structure and neuronal mechanisms of Cadherin-13 in relation to other cadherins and the cardiovascular system. An appraisal of various Cadherin-13-modulated signaling pathways impacting proliferation, migration and connectivity of specific neurons is also provided. Finally, we develop an integrative hypothesis of the mechanisms in which Cadherin-13 plays a central role in the regulation of brain network development, plasticity and function. The review concludes with emerging concepts about alterations in Cadherin-13 signaling contributing to the pathophysiology of neurodevelopmental disorders.